Compounds as cannabinoid receptor ligands and uses thereof

ABSTRACT

The present invention relates to compounds of formula (I), or pharmaceutical salts, prodrugs, salts of prodrugs, or combinations thereof, 
                         
wherein R 1 , R 2 , R 3 , R 4 , and L 1  are defined in the specification, compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions. The present invention also relates to compounds of formula (II), or pharmaceutical salts, prodrugs, salts of prodrugs, or combinations thereof,
 
                         
wherein R 1a , R 2a , R x , and n are as defined in the specification, compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.

This application claims priority to U.S. Ser. No. 60/989,492 filed onNov. 21, 2007 and is incorporated herein by reference in its entirety.The application is also a continuation-in-part of U.S. Ser. No.11/755,434 filed on May 30, 2007 which in turn seeks priority from U.S.Ser. No. 60/809,712, filed on May 31, 2006, all of which areincorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates to compounds that are cannabinoid receptorligands, compositions comprising such compounds, and methods of treatingconditions and disorders using such compounds and compositions.

BACKGROUND

(−)-Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), the major psychoactive constituentof marijuana, exerts a broad range of therapeutic effects through itsinteractions with two cannabinoid (CB) receptor subtypes, CB₁ and CB₂.CB₁ receptors are highly expressed in the central nervous system and toa lesser degree in the periphery in a variety of tissues of thecardiovascular and gastrointestinal systems. By contrast, CB₂ receptorsare most abundantly expressed in multiple lymphoid organs and cells ofthe immune system, including spleen, thymus, tonsils, bone marrow,pancreas and mast cells.

The psychotropic effects caused by Δ⁹-THC and other nonselective CBagonists are mediated by CB₁ receptors. These CB₁ receptor-mediatedeffects, such as euphoria, sedation, hypothermia, catalepsy, andanxiety, have limited the development and clinical utility ofnonselective CB agonists. Recent studies have demonstrated that CB₂modulators are analgesic in preclinical models of nociceptive andneuropathic pain without causing the adverse side effects associatedwith CB₁ receptor activation. Therefore, compounds that selectivelytarget CB₂ receptors are an attractive approach for the development ofnovel analgesics.

Pain is the most common symptom of disease and the most frequentcomplaint with which patients present to physicians. Pain is commonlysegmented by duration (acute vs. chronic), intensity (mild, moderate,and severe), and type (nociceptive vs. neuropathic).

Nociceptive pain is the most well known type of pain, and is caused bytissue injury detected by nociceptors at the site of injury. After theinjury, the site becomes a source of ongoing pain and tenderness. Thispain and tenderness are considered “acute” nociceptive pain. This painand tenderness gradually diminish as healing progresses and disappearwhen healing is complete. Examples of acute nociceptive pain includesurgical procedures (post-op pain) and bone fractures. Even though theremay be no permanent nerve damage, “chronic” nociceptive pain resultsfrom some conditions when pain extends beyond six months. Examples ofchronic nociceptive pain include osteoarthritis, rheumatoid arthritis,and musculoskeletal conditions (e.g., back pain), cancer pain, etc.

Neuropathic pain is defined as “pain initiated or caused by a primarylesion or dysfunction in the nervous system” by the InternationalAssociation for the Study of Pain. Neuropathic pain is not associatedwith nociceptive stimulation, although the passage of nerve impulsesthat is ultimately perceived as pain by the brain is the same in bothnociceptive and neuropathic pain. The term neuropathic pain encompassesa wide range of pain syndromes of diverse etiologies. The three mostcommonly diagnosed pain types of neuropathic nature are diabeticneuropathy, cancer neuropathy, and HIV pain. In addition, neuropathicpain is diagnosed in patients with a wide range of other disorders,including trigeminal neuralgia, post-herpetic neuralgia, traumaticneuralgia, phantom limb, as well as a number of other disorders ofill-defined or unknown origin.

Managing the spectrum of pain etiologies remains a major public healthproblem and both patients and clinicians are seeking improved strategiesto effectively manage pain. No currently available therapies or drugseffectively treat all types of nociceptive and neuropathic pain states.The compounds of the present invention are novel CB₂ receptor modulatorsthat have utility in treating pain, including nociceptive andneuropathic pain.

The location of CB₂ receptors on the surface of immune cells suggests arole for these receptors in immunomodulation and inflammation. Recentstudies have demonstrated that CB₂ receptor ligands haveimmunomodulatory and anti-inflammatory properties.

Accordingly, the need exists to further explore and develop CB₂ receptorligands that exhibit immunomodulatory and anti-inflammatory properties.These CB₂ receptors ligands will offer a unique pharmacotherapy for thetreatment of immune and inflammatory disorders.

SUMMARY

The present invention generally provides compounds that are CB₂ receptorligands and pharmaceutical compositions and methods for the treatment ofdisorders using these compounds and pharmaceutical compositions.

One aspect of the invention is directed towards compounds of formula(I), or pharmaceutical salts, prodrugs, salts of prodrugs, orcombinations thereof,

R₁ is alkoxyalkyl, alkoxyalkoxyalkyl, hydroxyalkyl, A, or A-alkylene-;

R₂ is hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkyl-S(O)₂—, aryl, arylalkyl, arylalkenyl,azidoalkyl, cyano, cycloalkyl, halo, haloalkyl, heteroaryl, heterocycle,—(CR₂₁R₂₂)_(m)—OH, R_(a)R_(b)N—, R_(a)R_(b)N-alkyl-, R_(c)R_(d)NC(O)—,or R₈—R₇—;

R₃ is hydrogen, alkoxy, alkoxyalkyl, alkyl, alkylcarbonyl, alkyl-S(O)₂—,aryl, arylalkyl, arylalkenyl, cyano, cycloalkyl, halo, haloalkyl,heteroaryl, heterocycle, —(CR₃₁R₃₂)_(m)—OH, R_(a)R_(b)N—,R_(a)R_(b)N-alkyl-, or R₈—R₇—; or

R₂ and R₃, together with the carbon atoms to which they are attached,form a 4-, 5-, 6-, or 7-membered monocyclic ring, optionally fused tobenzo or oxadiazole, said monocyclic ring contains zero or oneadditional double bond, zero or one oxygen atom, and zero or onenitrogen atom as ring atoms; two non-adjacent atoms of said monocyclicring are optionally linked by an alkenylene bridge of 2, 3, or 4 carbonatoms, or optionally linked by an alkylene bridge of 1, 2, 3, or 4carbon atoms, said monocyclic ring is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom the group consisting of oxo, alkyl, halo, —OH, —O(alkyl), andhaloalkyl; two substituents on the same carbon atom of said monocyclicring, together with the carbon atom to which they are attached,optionally form a 3-, 4-, 5-, or 6-membered monocyclic cycloalkyl ring,wherein the monocyclic cycloalkyl ring is optionally substituted with 1,2, 3, 4, 5, or 6 substituents independently selected from the groupconsisting of alkyl and haloalkyl; with the proviso that when R₂ and R₃,together with the carbon atom to which they are attached, form a ring asrepresented by formula (viii), (ix), or (xi),

then R₁ is A or A-alkylene-;

and with a further proviso that when R₂ and R₃ are other than forming aring with the carbon atoms to which they are attached, then R₁ isalkoxyalkoxyalkyl, A or A-alkylene-;

R₄ is alkyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocycle, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl,heteroarylalkyl, heterocyclealkyl, or R₁₀-L₂-R₉—; wherein the alkylgroup is optionally substituted with one substituent selected from thegroup consisting of alkoxy, alkoxycarbonyl, carboxy, halo, —OH, andR_(e)R_(f)N—;

R₇, R₈, and R₉, are each independently aryl, cycloalkyl, cycloalkenyl,heteroaryl, or heterocycle;

R₁₀ is aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycle, orcycloalkylalkyl;

R_(a) and R_(b), at each occurrence, are each independently hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, alkyl-S(O)₂—, or arylalkyl;

R_(e) and R_(d), are each independently hydrogen or alkyl;

R_(e) and R_(f), are each independently hydrogen, alkyl, oralkylcarbonyl;

A is a 4-, 5-, 6-, 7-, 8-, or 9-membered monocyclic heterocyclecontaining zero or one double bond, one or two oxygen, and zero or onenitrogen as ring atoms; two non-adjacent atoms of said heterocycle ringcan be optionally linked by an alkenylene bridge of 2, 3, or 4 carbonatoms, or optionally linked by an alkylene bridge of 1, 2, 3, or 4carbon atoms; or A is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl;each ring A is optionally fused with a monocyclic ring selected from thegroup consisting of benzo, cycloalkyl, cycloalkenyl, heterocycle andheteroaryl; and each A is independently unsubstituted or substitutedwith 1, 2, 3, 4, 5, or 6 substituents independently selected from thegroup consisting of oxo, alkyl, halo, —OH, —O(alkyl), and haloalkyl;

L₁ is a single bond or —NR_(g)—;

L₂ is a single bond, alkylene, or —O—;

R_(g) is hydrogen or alkyl;

the aryl, cycloalkyl, cycloalkenyl, heterocycle, or heteroaryl moieties,as a substituent, or as part of a substituent, as represented by R₂, R₃,R₄, R_(a), R_(b), R₇, R₈, R₉, and R₁₀, are each independentlyunsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl,alkyl-S(O)₂—, alkyl-S(O)₂—(CR₄₁R₄₂)_(p)═C(R₄₁)—,alkyl-S(O)₂—(CR₄₁R₄₂)_(p)—, alkyl-S—, alkyl-S—(CR₄₁R₄₂)_(p)—, alkynyl,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen,haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, —SH, N(O)₂,—C(R₄₁)═N—O(R₄₂), —(CR₄₁R₄₂)_(p)—C(R₄₁)═N—O(R₄₂), ═N—O(alkyl), ═N—OH,NZ₁Z₂—(CR₄₁R₄₂)_(p)—O—, —O—(CR₄₁R₄₂)_(p)-G₁, G₁, —NZ₁Z₂,—(CR₄₁R₄₂)_(p)—NZ₁Z₂, and (NZ₃Z₄)carbonyl;

G₁ is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containing onenitrogen atom and optionally 1 or 2 additional heteroatom in the ring,wherein said ring is attached to the parent moiety through the nitrogenatom, and said ring is optionally substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, ═N—CN, ═N—OR₅₁, —CN, oxo, —OR₅₁, —OC(O)R₅₁,—OC(O)N(R₅₁)₂, —S(O)₂R₅₂, —S(O)₂N(R₅₁)₂, —C(O)R₅₁, —C(O)OR₅₁,—C(O)N(R₅₁)₂, —N(R₅₁)₂, —N(R₅₁)C(O)R₅₁, —N(R₅₁)S(O)₂R₅₂,—N(R₅₁)C(O)O(R₅₂), —N(R₅₁)C(O)N(R₅₁)₂, —(CR_(1c)R_(1d))_(q)—OR₅₁,—(CR_(1c)R_(1d))_(q)—OC(O)R₅₁, —(CR_(1c)R_(1d))_(q)—OC(O)N(R₅₁)₂,—(CR_(1c)R_(1d))_(q)—S(O)₂R₅₂, —(CR_(1c)R_(1d))_(q)—S(O)₂N(R₅₁)₂,—(CR_(1c)R_(1d))_(q)—C(O)R₅₁, —(CR_(1c)R_(1d))₁—C(O)OR₅₁,—(CR_(1c)R_(1d))_(q)—C(O)N(R₅₁)₂, —(CR_(1c)R_(1d))_(q)—N(R₅₁)₂,—(CR_(1c)R_(1d))_(q)—N(R₅₁)C(O)R₅₁, —(CR_(1c)R_(1d))_(q)—N(R₅₁)S(O)₂R₅₂,—(CR_(1c)R_(1d))_(q)—N(R₅₁)C(O)O(R₅₂),—(CR_(1c)R_(1d))_(q)—N(R₅₁)C(O)N(R₅₁)₂, and —(CR_(1c)R_(1d))_(q)—CN;

R₅₁, at each occurrence, is independently hydrogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, —(CR_(2c)R_(2d))_(u)—OR⁵³, monocyclic cycloalkyl, or—(CR_(2c)R_(2d))_(u)-(monocyclic cycloalkyl); wherein R₅₃ is hydrogen,C₁-C₄ alkyl, C₁-C₄ haloalkyl, monocyclic cycloalkyl, or—(CR_(2c)R_(2d))_(u)-(monocyclic cycloalkyl);

R₅₂, at each occurrence, is independently C₁-C₄ alkyl, C₁-C₄ haloalkyl,monocyclic cycloalkyl, or —(CR_(2c)R_(2d))_(u)-(monocyclic cycloalkyl);

the monocyclic cycloalkyl moiety, as a substituent, or as part of asubstituent, as represented by R₅₁, R₅₂, and R₅₃ are each independentlyunsubstituted or substituted with 1, 2, 3, or 4 substituents selectedfrom the group consisting of C₁-C₄ alkyl, halo, hydroxy, C₁-C₄ alkoxy,C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl;

R₂₁, R₂₂, R₃₁, R₃₂, R₄₁, R₄₂, R_(1c), R_(1d), R_(2c) and R_(2d), at eachoccurrence, are each independently hydrogen, alkyl, haloalkyl, or halo;

m, p, q, and u, at each occurrence, are each independently 1, 2, 3, or4;

Z₁ and Z₂ are each independently hydrogen, alkyl, alkoxyalkyl,alkylcarbonyl, cyanoalkyl, haloalkyl, or formyl; and

Z₃ and Z₄ are each independently hydrogen, alkyl, haloalkyl, phenyl orbenzyl wherein the phenyl moiety is optionally substituted with 1, 2, 3,or 4 substituents selected from the group consisting of alkyl, hydroxyl,and haloalkyl.

Another aspect of the invention relates to compounds of formula (II), orpharmaceutical salts, prodrugs, salts of prodrugs, or combinationsthereof,

wherein

R_(1a) is alkoxyalkyl, hydroxyalkyl, alkyl, haloalkyl, orcycloalkylalkyl wherein the cycloalkyl moiety is optionally substitutedwith 1, 2, 3, 4, 5, or 6 substituents independently selected from thegroup consisting of oxo, alkyl, halo, —OH, —O(alkyl), and haloalkyl;

R_(2a) is hydrogen or alkyl;

R_(x) is an optional substituent of phenyl, selected from the groupconsisting of alkyl, alkylcarbonyl, alkoxy, alkoxyalkoxy, cyano, formyl,halogen, haloalkoxy, hydroxy, hydroxyalkyl, haloalkyl, ═N—OH,NZ_(1a)Z_(2a)—(CR_(41a)R_(42a))_(v)—O—, —O—(CR_(41a)R_(42a))_(v)-G_(1a),—(CR_(41a)R_(42a))_(v)-G_(1a), —(CR_(41a)R_(42a))_(v)—NZ_(1a)Z_(2a), andNZ_(1a)Z_(2a);

G_(1a) is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containingone nitrogen atom and optionally 1 or 2 additional heteroatom in thering, wherein said ring is attached to the parent moiety through thenitrogen atom, and said ring is optionally substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, ═N—CN, ═N—OR_(51a), —CN, oxo, —OR_(51a),—OC(O)R_(51a), —OC(O)N(R_(51a))₂, S(O)₂R_(52a), —S(O)₂N(R_(51a))₂,—C(O)R_(51a), —C(O)OR_(51a), —C(O)N(R_(51a))₂, —N(R_(51a))₂,—N(R_(51a))C(O)R_(51a), —N(R_(41a))S(O)₂R_(52a),—N(R_(51a))C(O)O(R_(52a)), —N(R_(51a))C(O)N(R_(51a))₂,—(CR_(1e)R_(1f))_(w)—OR₅₁, —(CR_(1e)R_(1f))_(w)—OC(O)R_(51a),—(CR_(1e)R_(1f))_(w)—OC(O)N(R_(51a))₂,—(CR_(1e)R_(1f))_(w)—S(O)₂R_(52a),—(CR_(1e)R_(1f))_(w)—S(O)₂N(R_(51a))₂),—(CR_(1e)R_(1f))_(w)—C(O)R_(51a), —(R_(1e)R_(1f))_(w)—C(O)OR_(51a),(CR_(1e)R_(1f))_(w)—C(O)N(R_(51a))₂, —(CR_(1e)R_(1f))_(w)—N(R_(51a))₂,—(CR_(1e)R_(1f))_(w)—N(R₅₁)C(O)R_(51a),—(CR_(1e)R_(1f))_(w)—N(R_(51a))S(O)₂R_(52a),—(CR_(1e)R_(1f))_(w)—N(R_(51a))C(O)O(R_(52a)),—(CR_(1e)R_(1f))_(w)—N(R_(51a))C(O)N)R_(51a))₂, and—(CR_(1e)R_(1f))_(w)—CN;

R_(51a), at each occurrence, is independently hydrogen, C₁-C₄ alkyl,C₁-C₄haloalkyl, —(CR_(2e)R_(2f))_(y)—OR⁵³, monocyclic cycloalkyl, or—(CR_(2e)R_(2f))_(y)-(monocyclic cycloalkyl); wherein R_(53a) ishydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, monocyclic cycloalkyl, or—(CR_(2e)R_(2f))_(y)-(monocyclic cycloalkyl);

R_(52a), at each occurrence, is independently C₁-C₄alkyl,C₁-C₄haloalkyl, monocyclic cycloalkyl, or—(CR_(2e)R_(2f))_(y)-(monocyclic cycloalkyl);

the monocyclic cycloalkyl moiety, as a substituent, or as part of asubstituent, as represented by R_(51a), R_(52a), and R_(53a) are eachindependently unsubstituted or substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₄ alkyl, halo,hydroxy, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl;

R_(41a), R_(42a), R_(1e), R_(1f), R_(2e), and R_(2f), at eachoccurrence, are each independently hydrogen, alkyl, haloalkyl, or halo;

v, w, and y, at each occurrence, are each independently 1, 2, 3, or 4;

Z_(1a) and Z_(2a) are each independently hydrogen, alkyl, alkoxyalkyl,alkylcarbonyl, cyanoalkyl, haloalkyl, or formyl; and

n is 1, 2, 3, 4, or 5.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof the invention or a pharmaceutically acceptable salt thereof incombination with one or more pharmaceutically acceptable carriers. Suchcompositions can be administered in accordance with a method of theinvention, typically as part of a therapeutic regimen for treatment orprevention of conditions and disorders related to cannabinoid (CB)receptor subtype, CB₂. More particularly, the method is useful fortreating conditions related to neuropathic pain, nociceptive pain,inflammatory pain, inflammatory disorders, immune disorders,neurological disorders, cancers of the immune system, respiratorydisorders, obesity, diabetes, cardiovascular disorders, or for providingneuroprotection.

Further, the present invention provides the use of compounds of thepresent invention or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of the disease conditionsdescribed above, alone or in combination with one or morepharmaceutically acceptable carrier(s), particularly for the treatmentof neuropathic pain, nociceptive pain, inflammatory pain, or combinationthereof.

The compounds, compositions comprising the compounds, and methods fortreating or preventing conditions and disorders by administering thecompounds are further described herein.

These and other objects of the invention are described in the followingparagraphs. These objects should not be deemed to narrow the scope ofthe invention.

DETAILED DESCRIPTION

Compounds of formulae (I) and (II) are disclosed in this invention,

wherein R₁, R₂, R₃, R₄, L₁, R_(1a), R_(2a), R_(x), and n are as definedabove in the Summary of the Invention and below in the DetailedDescription. Compositions comprising such compounds and methods fortreating conditions and disorders using such compounds and compositionsare also disclosed.

In various embodiments, the present invention provides at least onevariable that occurs more than one time in any substituent or in thecompound of the invention or any other formulae herein. Definition of avariable on each occurrence is independent of its definition at anotheroccurrence. Further, combinations of substituents are permissible onlyif such combinations result in stable compounds. Stable compounds arecompounds, which can be isolated from a reaction mixture.

a. DEFINITIONS

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond. Representative examples of alkenyl include,but are not limited to, ethenyl(vinyl), 2-propenyl, 2-methyl-2-propenyl,3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and3-decenyl.

The term “alkenylene” denotes a divalent group derived from a straightor branched chain hydrocarbon of 2, 3, or 4 carbon atoms and contains atleast one carbon-carbon double bond. Representative examples ofalkenylene include, but are not limited to, —CH═CH— and —CH₂CH═CH—.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.The term “C₁-C₄ alkoxy” a C₁-C₄ alkyl group, as defined herein, appendedto the parent molecular moiety through an oxygen atom. Representativeexamples of alkoxy include, but are not limited to, methoxy, ethoxy,propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,3-methoxy-3-methylbutoxy, 2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkoxyalkyl” as used herein, means an alkoxyalkoxygroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkoxyalkoxyalkyl include, but are not limited to,tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy)methyl,and 2-(2-methoxyethoxy)ethyl.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, methoxymethyl, 2-methoxy-2-methylpropyl, and3-methoxypropyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkoxycarbonylalkyl include, but are not limited to,ethoxycarbonylmethyl, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl,and 2-tert-butoxycarbonylethyl.

The term “alkyl” as used herein, means a straight or branched saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term “C₁₋₆alkyl” or “C₁-C₆ alkyl” means a straight or branched saturatedhydrocarbon chain containing from 1 to 6 carbon atoms. The term “C₁-C₄alkyl” means a straight or branched saturated hydrocarbon chaincontaining from 1 to 4 carbon atoms. Representative examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl, 1-methylbutyl, 1-methylethyl, 2-methylbutyl,3-methylbutyl, 1-methylpropyl, 1-ethylpropyl, 2-methylpropyl,1,1-dimethylethyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl, 1,2,2-trimethylpropyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonylalkyl” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein.

Representative examples of alkylcarbonylalkyl include, but are notlimited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and3-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylene” means a divalent group derived from a straight orbranched saturated hydrocarbon chain of 1 to 10 carbon atoms. The term“C₁-C₆ alkylene” means a divalent group derived from a straight orbranched saturated hydrocarbon chain of 1 to 6 carbon atoms. The term“C₁-C₃ alkylene” means a divalent group derived from a straight orbranched saturated hydrocarbon chain of 1 to 3 carbon atoms. The term“C₁-C₂ alkylene” means a divalent group derived from a straight orbranched saturated hydrocarbon chain of 1 to 2 carbon atoms.Representative examples of alkylene include, but are not limited to,—CH₂—, —CH(CH₃)—, —CH(C₂H₅), —CH(CH(CH₃)(C₂H₅))—, —C(H)(CH₃)CH₂CH₂—,—C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkylsulfinyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfinyl group, as defined herein. Representative examples ofalkylsulfinyl include, but are not limited to, methylsulfinyl andethylsulfinyl.

The term “alkylsulfinylalkyl” as used herein, means an alkylsulfinylgroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofalkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyland ethylsulfinylmethyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,1-propyl-pent-3-ynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl,” as used herein, means phenyl, a bicyclic aryl, or atricyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to amonocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl.Representative examples of the bicyclic aryl include, but are notlimited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, andtetrahydronaphthalenyl. The tricyclic aryl is exemplified by a bicyclicaryl fused to a monocyclic cycloalkyl, or a bicyclic aryl fused to amonocyclic cycloalkenyl, or a bicyclic aryl fused to a phenyl.Representative examples of tricyclic aryl ring include, but are notlimited to, anthracene, phenanthrene, dihydroanthracenyl, fluorenyl,1,2-dihydroacenaphthylenyl (including 1,2-dihydroacenaphthylen-5-yl),and tetrahydrophenanthrenyl. The phenyl, bicyclic and tricyclic arylsare attached to the parent molecular moiety through any carbon atomcontained within the phenyl, bicyclic, and tricyclic aryls respectively.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of arylalkyl include,but are not limited to, benzyl, 2-phenylethyl, 1-methyl-3-phenylpropyl,2-methyl-1-phenylbutyl, 1-phenylpropyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “azido” as used herein, means a —N₃ group.

The term “azidoalkyl” as used herein, means an azido group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —CO₂H group.

The term “carboxyalkyl” as used herein, means a carboxy group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. Representative examples ofcarboxyalkyl include, but are not limited to, carboxymethyl,2-carboxyethyl, and 3-carboxypropyl.

The term “cyano” as used herein, means a —CN group.

The term “cyanoalkyl” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of cyanoalkyl include,but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkenyl” as used herein, means a monocyclic or bicyclicring system containing zero heteroatoms in the ring. The monocycliccycloalkenyl has three, four, five, six, seven or eight carbon atoms andzero heteroatoms. The three or four-membered ring systems have onedouble bond, the five- or six-membered ring systems have one or twodouble bonds, and the seven- or eight-membered ring systems have one,two or three double bonds. Representative examples of monocyclic ringsystems include, but are not limited to, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and 3-cyclopenten-1-yl.Bicyclic ring systems are exemplified by a monocyclic cycloalkenyl ringfused to a monocyclic cycloalkyl ring, or a monocyclic cycloalkenyl ringfused to a monocyclic cycloalkenyl ring. Representative examples ofbicyclic ring systems include, but are not limited to3a,4,5,6,7,7a-hexahydro-1H-indenyl, 4,5,6,7-tetrahydro-3aH-indene, andoctahydronaphthalenyl. The monocyclic or the bicyclic cycloalkenyl ringcan be appended to the parent molecular moiety through any substitutablecarbon atom within the monocyclic or the bicyclic cycloalkenyl.

The term “cycloalkenylalkyl” as used herein, means a cycloalkenyl groupas defined herein, appended to the parent molecular moiety through analkylene group, as defined herein.

The term “cycloalkyl” as used herein, means a monocyclic, or a bicyclicring system, or a spirocyclic cycloalkyl. The monocyclic cycloalkyl is acarbocyclic ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms,zero heteroatoms and zero double bonds. Examples of monocyclic ringsystems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Bicyclic ring systems are exemplified by amonocyclic cycloalkyl ring fused to a monocyclic cycloalkyl ring.Representative examples of bicyclic ring systems include, but are notlimited to, bicyclo[4.1.0]heptane, bicyclo[6.1.0]nonane,octahydroindene, and decahydronaphthalene. Spirocyclic cycloalkyl isexemplified by a monocyclic cycloalkyl ring wherein two of thesubstituents on the same carbon atom of the ring, together with saidcarbon atom, form a 4-, 5-, or 6-membered monocyclic cycloalkyl. Anexample of a spirocyclic cycloalkyl is spiro[2.5]octane. The monocyclic,bicyclic and spirocyclic cycloalkyl groups of the present invention canbe appended to the parent molecular moiety through any substitutablecarbon atom of the groups. The monocyclic and bicyclic cycloalkyl groupsof the present invention, with the exception of R⁴, may contain one ortwo alkylene bridges of 1, 2, 3, or 4 carbon atoms, each of whichlinking two non adjacent carbon atoms of the group. Examples of such abridged system include, but are not limited to, adamantane(tricyclo[3.3.1.1^(3,7)]decane) and bicyclo[2.2.1]heptane.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein.

Representative examples of cycloalkylalkyl include, but are not limitedto, cyclopentylmethyl, cyclohexylmethyl, cyclopropylmethyl, and1-cyclopropylethyl.

The term “formyl” as used herein, means a —C(O)H group.

The term “formylalkyl” as used herein, means a formyl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of formylalkylinclude, but are not limited to, formylmethyl and 2-formylethyl.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means an alkoxy group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. The term “C₁-C₄ haloalkoxy” as used herein, means aC₁-C₄ alkoxy group, as defined herein, in which one, two, three, four,five or six hydrogen atoms are replaced by halogen. Representativeexamples of haloalkoxy include, but are not limited to,trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and2,2-difluoroethoxy.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, or seven hydrogenatoms are replaced by halogen. The term “C₁-C₄ haloalkyl” as usedherein, means a C₁-C₄ alkyl group, as defined herein, in which one, two,three, four, five, or six hydrogen atoms are replaced by halogen.Representative examples of haloalkyl include, but are not limited to,chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, trifluoromethyl,2,2,2-trifluoroethyl, difluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, and 2-iodoethyl.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora bicyclic heteroaryl.

The monocyclic heteroaryl is a 5 or 6 membered ring containing at leastone heteroatom independently selected from the group consisting of O, N,and S. The 5-membered ring contains two double bonds, and one, two,three, or four heteroatoms as ring atoms. The 6-membered ring containsthree double bonds, and one, two, three or four heteroatoms as ringatoms. Representative examples of monocyclic heteroaryl include, but arenot limited to, furanyl (including furan-3-yl, furan-2-yl), imidazolyl,isoxazolyl (including isoxazol-5-yl), isothiazolyl, oxadiazolyl(including 1,2,4-oxadiazol-3-yl), oxazolyl (including 1,3-oxazol-2-yl),pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl),pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl (including pyrazol-5-yl),pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl (includingthien-2-yl), triazolyl, and triazinyl. The bicyclic heteroaryl isexemplified by a monocyclic heteroaryl fused to phenyl, or a monocyclicheteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroarylfused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused toa monocyclic heteroaryl, or a monocyclic heteroaryl fused to amonocyclic heterocycle. Representative examples of bicyclic heteroarylinclude, but are not limited to, benzofuranyl (includingbenzofuran-5-yl), benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl,benzodioxolyl, benzothienyl, chromenyl, cinnolinyl, furopyridinyl,indolyl, indazolyl, isoindolyl, isoquinolinyl (includingisoquinolin-5-yl), naphthyridinyl, oxazolopyridine, quinolinyl(including quinolin-4-yl, quinolin-5-yl, quinolin-8-yl), thienopyridinyland thienopyridinyl. The monocyclic and the bicyclic heteroaryl groupsare connected to the parent molecular moiety through any substitutablecarbon atom or any substitutable nitrogen atom contained within thegroups. The nitrogen and sulfur heteroatoms of the heteroaryl rings mayoptionally be oxidized, and are contemplated within the scope of theinvention.

The term “heteroarylalkyl” as used herein, means a heteroaryl group asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. An example of heteroarylalkyl is3-thienylpropyl.

The term “heterocycle” or “heterocyclic” as used herein, refers to amonocyclic, bicyclic, tricyclic, or a spirocyclic ring system,containing at least one heteroatom. The monocyclic heterocycle is a 3,4, 5, 6, 7, or 8-membered ring containing at least one heteroatomindependently selected from the group consisting of O, N, and S. The 3or 4 membered ring contains 1 heteroatom selected from the groupconsisting of O, N and S, and optionally one double bond. The 5-memberedring contains zero or one double bond, and one, two or three heteroatomsin the ring selected from the group consisting of O, N and S. The 6, 7,or 8-membered ring contains zero, one, or two double bonds, and one,two, or three heteroatoms in the ring selected from the group consistingof O, N and S. Representative examples of monocyclic heterocycleinclude, but are not limited to, azetidinyl (including azetidin-3-yl),azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl,1,3-dioxolanyl, 4,5-dihydroisoxazol-5-yl, dihydropyranyl (including3,4-dihydro-2H-pyran-6-yl), 1,3-dithiolanyl, 1,3-dithianyl,imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl,oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl (pyrrolidin-3-yl), tetrahydrofuranyl (includingtetrahydrofuran-2-yl tetrahydrofuran-3-yl), tetrahydropyranyl (includingtetrahydro-2H-pyran-4-yl), tetrahydropyridinyl (including1,2,3,6-tetrahydropyridin-4-yl), tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, andtrithianyl. The bicyclic heterocycle of the present invention isexemplified by a monocyclic heterocycle fused to a phenyl group, or amonocyclic heterocycle fused to a monocyclic cycloalkyl group, or amonocyclic heterocycle fused to a monocyclic cycloalkenyl group, or amonocyclic heterocycle fused to a monocyclic heterocycle group.Representative examples of bicyclic heterocycle include, but are notlimited to, 1,3-benzodioxolyl (including 1,3-benzodioxol-4-yl),1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, dihydrobenzofuranyl(including 2,3-dihydro-1-benzofuran-7-yl), 2,3-dihydro-1-benzothienyl,2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl. Spirocyclicheterocycle means a 4,5-, 6-, 7-, or 8-membered monocyclic heterocyclering wherein two of the substituents on the same carbon atom form a 4-,5-, or 6-membered monocyclic cycloalkyl, wherein the cycloalkyl isoptionally substituted with 1, 2, 3, 4, or 5 alkyl groups. One exampleof a spiroheterocycle is 5-oxaspiro[3,4]octane. The tricyclicheterocycle is a bicyclic heterocycle fused to a phenyl, or a bicyclicheterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocyclefused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to amonocyclic heterocycle. Representative examples of tricyclic heterocycleinclude, but are not limited to, 2,3,4,4a,9,9a-hexahydro-1H-carbazolyl,5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl, and5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl. The monocyclic, bicyclic,tricyclic, and spirocyclic heterocycle groups, unless otherwise noted,are connected to the parent molecular moiety through any substitutablecarbon atom or any substitutable nitrogen atom contained within thegroup. The nitrogen and sulfur heteroatoms in the heterocycle rings mayoptionally be oxidized and the nitrogen atoms may optionally bequarternized.

The term “heterocyclealkyl” as used herein, means a heterocycle group asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein. An example includes, but is notlimited to, tetrahydropyranmethyl (includingtetrahydro-2H-pyran-4-ylmethyl).

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxy-3-methylbutyl,2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

The term “hydroxy-protecting group” or “O-protecting group” means asubstituent which protects hydroxy groups against undesirable reactionsduring synthetic procedures. Examples of hydroxy-protecting groupsinclude, but are not limited to, substituted methyl ethers, for example,methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)-ethoxymethyl, benzyl, and triphenylmethyl;tetrahydropyranyl ethers; substituted ethyl ethers, for example,2,2,2-trichloroethyl and t-butyl; silyl ethers, for example,trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclicacetals and ketals, for example, methylene acetal, acetonide andbenzylidene acetal; cyclic ortho esters, for example, methoxymethylene;cyclic carbonates; and cyclic boronates. Commonly usedhydroxy-protecting groups are disclosed in T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, New York (1999).

The term “nitrogen protecting group” as used herein, means those groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Preferred nitrogen protecting groups are acetyl,benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl,tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl, andtriphenylmethyl(trityl).

The term “oxo” as used herein, means a ═O moiety.

The term “sulfinyl” as used herein, means a —S(O)— group.

The term “tautomer” as used herein means a proton shift from one atom ofa compound to another atom of the same compound wherein two or morestructurally distinct compounds are in equilibrium with each other.

b. COMPOUNDS

Compounds of the invention have the formula (I) as described above.

Particular values of variable groups in compounds of formula (I) are asfollows. Such values may be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter. In compounds of formula (I), R₁ is alkoxyalkyl,alkoxyalkoxyalkyl, hydroxyalkyl, A, or A-alkylene- wherein A is asdisclosed in the Summary. Embodiments of the present invention includecompounds wherein R₁ is A or A-alkylene- and A is a 4-, 5-, 6-, 7-, 8-,or 9-membered monocyclic heterocycle containing zero or one double bond,and one or two oxygen and zero or one nitrogen as ring atoms; twonon-adjacent atoms of said heterocycle ring can be optionally linked byan alkenylene bridge of 2, 3, or 4 carbon atoms, or optionally linked byan alkylene bridge of 1, 2, 3, or 4 carbon atoms, each ring A isoptionally fused with a monocyclic ring selected from the groupconsisting of benzo, cycloalkyl, cycloalkenyl, heterocycle, andheteroaryl, and each Ring A is optionally substituted as described inthe Summary. Some examples of Ring A are those that are represented byformula (i), (ii), (iii), (iv), (v), (vi), (vii), and (viia) whereineach ring is independently unsubstituted or substituted as described inthe Summary. Certain examples of the optional substituents of Ring Ainclude, but are not limited to, alkyl such as C₁₋₆ alkyl (for example,methyl, ethyl), haloalkyl (e.g. trifluoromethyl), and oxo.

Examples of compounds of the invention include, but are not limited to,those wherein R₁ is oxetan-2-ylmethyl, oxetan-3-ylmethyl,tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl,tetrahydro-2H-pyran-2-ylmethyl, tetrahydro-2H-pyran-3-ylmethyl,tetrahydro-2H-pyran-4-ylmethyl, 2-tetrahydro-2H-pyran-4-ylethyl,1,3-dioxolan-2-ylmethyl, 2-1,3-dioxolan-2-ylethyl,1,3-dixoxolan-4-ylmethyl, 4,5-dihydroisoxazol-5-ylmethyl,1,4-dioxan-2-ylmethyl, 2-morpholin-4-ylethyl, tetrahydro-2H-pyran-4-yl,and 1,3-oxazolidin-4-ylmethyl, wherein each of the oxetan-2-yl,oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl,tetrahydro-2H-pyran-4-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,4,5-dihydroisoxazol-5-yl, 1,4-dioxan-2-yl, morpholin-4-yl, and1,3-oxazolidin-4-yl, is each independently unsubstituted or substitutedwith 1, 2, 3, or 4 substituents selected from the group consisting ofalkyl (for example, methyl, ethyl), haloalkyl (e.g. trifluoromethyl),and oxo.

Yet other examples of compounds of formula (I) include those wherein R₁is A-alkylene- and A is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl,each of which is optionally substituted as described in the Summary. Forexample R₁ is furanylmethyl, oxazolylmethyl, isoxazolylmethyl, oroxadiazolylmethyl, wherein each of the furanyl, oxazolyl, isoxazolyl andoxadiazolyl is optionally substituted with the group consisting of alkyl(e.g. methyl, ethyl), halo, and haloalkyl (e.g. trifluoromethyl).

The alkylene moiety of A-alkylene-, for example, is C₁-C₆ alkylene.Further examples of the alkylene moiety of A-alkylene- is C₁-C₃alkylene. Yet further examples of the alkylene moiety of A-alkylene- isC₁-C₂ alkylene.

Other examples of compounds of formula (I) include those wherein R₁ isalkoxyalkyl (e.g. 2-ethoxyethyl, 2-methoxymethyl,2-methoxy2-methylpropyl, 3-methoxypropyl), alkoxyalkoxyalkyl (e.g.2-(2-methoxyethoxy)ethyl), or hydroxyalkyl (e.g.3-hydroxy-3-methylbutyl).

R₂ is hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkyl-S(O)₂—, aryl, arylalkyl, arylalkenyl,azidoalkyl, cyano, cycloalkyl, halo, haloalkyl, heteroaryl, heterocycle,—(CR₂₁R₂₂)_(m)—OH, R_(a)R_(b)N—, R_(a)R_(b)N-alkyl-, R_(a)R_(a)NC(O)—,or R₈—R₇—; wherein R₂₁, R₂₂, m, R_(a), R_(b), R_(e), R_(d), R₇, and R₈,and the optional substituents of the aryl, cycloalkyl, heteroaryl andheterocycle moieties are as described in the Summary. Certain examplesof compounds of formula (I) include those wherein R₂ is hydrogen,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl (for example, methyl, ethyl,propyl, tert-butyl), aryl (for example, optionally substituted phenyl),halo, haloalkyl (e.g. trifluoromethyl), or —(CR₂₁R₂₂)_(m)—OH; whereinR₂₁, R₂₂, and m, and the optional substituents of the aryl moiety are asdisclosed in the Summary. For example, the optional substituents of thearyl moiety are selected from the group consisting of alkyl and halo.Included, but not limited to, are compounds of formula (I) in which R₂₁and R₂₂ are the same or different, and are each independently hydrogen,methyl, or ethyl, and m is 1. Embodiments of the present inventioninclude compounds in which R₂ is hydrogen or alkyl (for example, methyl,ethyl, propyl, tert-butyl).

R₃ is hydrogen, alkoxy, alkoxyalkyl, alkyl, alkylcarbonyl, alkyl-S(O)₂—,aryl, arylalkyl, arylalkenyl, cyano, cycloalkyl, halo, haloalkyl,heteroaryl, heterocycle, —(CR₃₁R₃₂)_(m)—OH, R_(a)R_(b)N—,R_(a)R_(b)N-alkyl-, or R₈—R₇—; wherein R₃₁, R₃₂, m, R_(a), R_(b), R₇,and R₈, and the optional subtituents of the aryl, cycloalkyl, heteroaryland heterocycle moieties are as disclosed in the Summary. Examples ofcompounds of formula (I) include, but are not limited to, those whereinR₃ is hydrogen, alkyl (for example, methyl, ethyl, n-propyl,tert-butyl), alkylcarbonyl (e.g. acetyl), aryl (for example, optionallysubstituted phenyl), cycloalkyl (for example, cyclopropyl, cyclohexyl,each of which is optionally substituted), halo, haloalkyl (e.g.trifluoromethyl), heterocycle (for example, morpholinyl), or—(CR₃₁R₃₂)_(m)—OH, wherein R₃₁, R₃₂, and m are as disclosed in theSummary. The optional substituents of aryl, cycloalkyl, and heterocyclemoieties are as disclosed in the Summary, for example, the optionalsubstituents are selected from the group consisting of alkyl (e.g.methyl), haloalkyl (e.g. trifluoromethyl), and halo. Non limitingexamples of R₃₁ and R₃₂ (R₃₁ and R₃₂ can be the same or different) arealkyl (for example, methyl) or haloalkyl (for example, 2-iodoethyl,trifluoromethyl). m, for example, is 1. Embodiments of the presentinvention include compounds in which R₃ is alkyl (for example, methyl,ethyl, n-propyl, or tert-butyl) or —(CR₃₁R₃₂)_(m)—OH. Other examplesinclude those wherein R₃ is —(CR₃₁R₃₂)_(m)—OH, wherein m is 1, and R₃₁and R₃₂ are alkyl (such as, but not limited to, methyl) or haloalkyl(such as, but not limited to, trifluoromethyl).

In another embodiment, R₂ and R₃, together with the carbon atoms towhich they are attached, form a 4-, 5-, 6-, or 7-membered monocyclicring as described in the Summary. Embodiments of the present inventioninclude compounds of formula (I) wherein R₂ and R₃, together with thecarbon atoms to which they are attached, form a monocyclic ring asdescribed in the Summary, containing zero heteroatoms in said monocyclicring. Formulae (viii), (ix), (ixa), (xi), (xii), (xiii), and (xiv), eachof which is optionally substituted as described in the Summary,represent some of these rings formed by R₂, R₃, and the carbon atoms towhich they are attached, with the proviso that when said ring isrepresented by (viii), (ix) or (xi), then R₁ is A or A-alkylene, whereinA is as described in the Summary and the Detailed Description sections.

Yet other compounds of the present invention include those wherein R₂and R₃, together with the carbon atoms to which they are attached, forma 4-, 5-, 6-, or 7-membered monocyclic ring optionally fused to benzo oroxadiazole, said monocyclic ring contains zero or one additional doublebond, zero oxygen atom and zero nitrogen atom as ring atoms; and twonon-adjacent atoms of said monocyclic ring are linked by an alkenylenebridge of 2, 3, or 4 carbon atoms, or linked by an alkylene bridge of 1,2, 3, or 4 carbon atoms. Examples include, but are not limited to,formulae (xii), (xiii) and (xiv), each of which is optionallysubstituted.

Further examples of compounds of formula (I) include, but are notlimited to, those wherein R₂ and R₃, together with the carbon atoms towhich they are attached, form a monocyclic ring containing zeroadditional double bond, zero oxygen and zero nitrogen atom, such asthose represented by (viii), (ix) or (xi).

Yet other compounds of the present invention include those wherein R₂and R₃, together with the carbon atoms to which they are attached, forma 4-, 5-, 6-, or 7-membered monocyclic ring optionally fused to benzo oroxadiazole, said monocyclic ring contains zero or one additional doublebond, and one oxygen atom and zero or one nitrogen atom as ring atoms;and two non-adjacent atoms of said monocyclic ring are optionally linkedby an alkenylene bridge of 2, 3, or 4 carbon atoms, or optionally linkedby an alkylene bridge of 1, 2, 3, or 4 carbon atoms. Examples include,but are not limited to, formula (xv)-(xxix), particularly, (xv), (xviii)and ((xxix).

Each ring formed by R₂, R₃, and the carbon atoms to which they areattached is independently unsubstituted or substituted as described inthe Summary, for example, these rings can be independently unsubstitutedor substituted with 1, 2, 3, 4, 5 or 6 substituents independentlyselected from alkyl such as C₁₋₆ alkyl (for example, methyl), hydroxy,and oxo. Such rings are optionally fused with benzo or oxadiazole.Examples of such an optionally substituted fused ring are represented byformula (x) and (xa).

R₄ is alkyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocycle, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl,heteroarylalkyl, heterocyclealkyl, or R₁₀-L₂-R₉—; wherein the alkylgroup is optionally substituted with one substituent selected from thegroup consisting of alkoxy, alkoxycarbonyl, carboxy, halo, —OH, andR_(e)R_(f)N—; R₉, R₁₀, R_(e), and R_(f), and the aryl moiety, cycloalkylmoiety, cycloalkenyl moiety, heteroaryl moiety and the heterocyclemoiety are independently unsubstituted or substituted as described inthe Summary. In one embodiment, R₄ is optionally substituted aryl. Inanother embodiment, R₄ is phenyl or naphthyl, each of which isoptionally substituted. Yet other examples of compounds of formula (I)are those wherein R₄ is arylalkyl wherein the aryl moiety is optionallysubstituted. Other examples of compounds of formula (I) are thosewherein R₄ is heteroaryl (for example, quinolinyl, isoquinolinyl,benzofuranyl, thienyl, pyrazolyl, pyridinyl), heterocycle(tetrahydropyranyl, dihydropyranyl, 2,3-dihydrobenzofuranyl,1,3-benzodioxolyl), heteroarylalkyl (e.g. 3-thien-2-ylpropyl), orheterocyclealkyl (for example, tetrahydro-2H-pyranylmethyl), each of theheterocycl and heteroaryl moieties is optionally substituted asdescribed in the Summary. Yet other examples are those wherein R₄ isalkynyl. Other examples are those wherein R₄ is alkyl optionallysubstituted with R_(e)R_(f)N—, —OH, or alkoxycarbonyl, wherein R_(e) andR_(f) are as disclosed in the Summary. Further examples are thosewherein R₄ is cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, spiro[2.5]octane) or cycloalkylalkyl (e.g.cyclopentylmethyl, cyclohexylmethyl) wherein the cycloalkyl moiety isoptionally substituted.

Yet other examples of compounds of formula (I) are those wherein R₄ isR₁₀-L₂-R₉— wherein R₉ is aryl (for example, phenyl, naphthyl) orheteroaryl (e.g. pyrazolyl), L₂ is alkylene (e.g. CH₂, CH₂CH₂), and R₁₀is heterocycle (e.g. tetrahydrofuranyl, azetidinyl, pyrrolidinyl,morpholinyl, thiomorpholinyl, piperazinyl) or aryl (e.g. phenyl); inother embodiments, R₉ is aryl (for example, phenyl, naphthyl) orheteroaryl (e.g. pyrazolyl), L₂ is O, and R₁₀ iscycloalkyl(cyclopropyl), cycloalkylalkyl (e.g. cyclopropylmethyl,cyclopentylmethyl), or heterocycle (e.g. tetrahydrofuranyl, azetidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl). Each R₉ andR₁₀ is optionally substituted as described in the Summary andembodiments herein.

Examples of the optional substituents of R₄ and R₁₀ include, but are notlimited to, alkyl (for example, methyl, ethyl), alkylcarbonyl (forexample, acetyl), alkylcarbonylalkyl (e.g. acetylmethyl), alkoxy (forexample, methoxy, ethoxy, isopropoxy, tert-butyoxy), alkoxyalkoxy (forexample, 2-methoxyethoxy, 3-methyl-3-methoxybutoxy), alkoxycarbonyl(e.g. methoxycarbonyl), cyano, formyl, halogen (for example, Cl, Br, I,F), haloalkoxy (for example, trifluoromethoxy, difluoromethoxy,2,2,2-trifluoroethoxy), hydroxy, haloalkyl (e.g. trifluoromethyl),alkyl-S(O)₂—(CR₄₁R₄₂)_(p)═C(R₄₁)—, alkyl-S(O)₂—(CR₄₁R₄₂)_(p)—, alkyl-S—(e.g. CH₃—S—), alkenyl (e.g. vinyl), oxo, —C(R₄₁)═N—O(R₄₂),—(CR₄₁R₄₂)_(p)—C(R₄₁)═N—O(R₄₂), ═N—O(alkyl), NZ₁Z₂—(CR₄₁R₄₂)_(p)—O—,—O—(CR₄₁R₄₂)_(p)-G₁, G₁, —NZ₁Z₂, and —(CR₄₁R₄₂)_(p)—NZ₁Z₂, wherein Z₁,Z₂, R₄₁, R₄₂, p, and G₁ are as described in the Summary. For example,R₄₁ and R₄₂ are the same or different, and at each occurrence, are eachindependently hydrogen or alkyl (e.g. methyl, ethyl). p, for example, is1, 2, or 3. Z₁ and Z₂, are the same or different, and at eachoccurrence, are each, for example, independently hydrogen, alkyl (e.g.methyl, ethyl, tert-butyl), cyanoalkyl (e.g. cyanomethyl), oralkoxyalkyl (e.g. 2-methoxyethyl). G₁, for example, is morpholinyl,1,2,3,6-tetrahydropyridinyl, piperidinyl, or thiomorpholinyl, each ofwhich is optionally substituted as described in the Summary, forexample, optionally substituted with 1, 2, or 3 substituents selectedfrom alkyl (e.g. methyl), oxo, alkoxycarbonyl (e.g.tert-butoxycarbonyl). Examples of the optional substituents of R₉include, but are not limited to, alkyl (e.g. methyl, tert-butyl, ethyl),haloalkyl (e.g. trifluoromethyl), and halogen.

L₁ is a single bond or —NR_(g)— wherein R_(g) is hydrogen or alkyl.Certain compounds of the present invention include those wherein L₁ is asingle bond. Yet others are those wherein L₁ is —NR_(g)— wherein R_(g)is hydrogen or alkyl. Other examples include those wherein L₁ is —NH—.

It is appreciated that the present invention contemplates compounds offormula (I) with combinations of the above embodiments, includingparticular, more particular and preferred embodiments.

Accordingly, one aspect of the invention relates to a group of compoundsof formula (I), or pharmaceutically acceptable salts thereof, wherein R₁is A or A-alkylene-, R₂ is hydrogen, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl (for example, methyl, ethyl, propyl,tert-butyl), aryl (for example, optionally substituted phenyl), halo,haloalkyl (e.g. trifluoromethyl), or —(CR₂₁R₂₂)_(m)—OH; R₃ is hydrogen,alkyl (for example, methyl, ethyl, n-propyl, tert-butyl), alkylcarbonyl(e.g. acetyl), aryl (for example, optionally substituted phenyl),cycloalkyl (for example, cyclopropyl, cyclohexyl, each of which isoptionally substituted), halo, haloalkyl (e.g. trifluoromethyl),heterocycle (for example, morpholinyl), or —(CR₃₁R₃₂)_(m)—OH; A is a 4-,5-, 6-, 7-, 8-, or 9-membered monocyclic heterocycle containing zero orone double bond, one or two oxygen, and zero or one nitrogen as ringatoms; two non-adjacent atoms of each A can be optionally linked by analkenylene bridge of 2, 3, or 4 carbon atoms, or optionally linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms; each ring A is optionallyfused with a monocyclic ring selected from the group consisting ofbenzo, cycloalkyl, cycloalkenyl, heterocycle, and heteroaryl; and each Ais independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from the group consisting of oxo,alkyl, halo, —OH, —O(alkyl), and haloalkyl; and L₁, R₄, R₂₁, R₂₂, R₃₁,R₃₂, m; and the optional substituents of the aryl, cycloalkyl, andheterocycle moieties are as disclosed in the Summary and the DetailedDescription. Ring A, for example, is formula (i), (ii), (iii), (iv),(v), (vi), (vii), or (viia), wherein each ring is independentlyunsubstituted or substituted as described in the Summary and DetailedDescription. The alkylene moiety of A-alkylene-, for example, is C₁-C₆alkylene. Further examples of the alkylene moiety of A-alkylene- isC₁-C₃ alkylene. Yet further examples of the alkylene moiety ofA-alkylene- is C₁-C₂ alkylene. Further examples of R₁ as A or A-alkyleneinclude, but are not limited to, oxetan-2-ylmethyl, oxetan-3-ylmethyl,tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl,tetrahydro-2H-pyran-2-ylmethyl, tetrahydro-2H-pyran-3-ylmethyl,tetrahydro-2H-pyran-4-ylmethyl, 2-tetrahydro-2H-pyran-4-ylethyl,1,3-dioxolan-2-ylmethyl, 2-1,3-dioxolan-2-ylethyl,1,3-dioxolan-4-ylmethyl, 4,5-dihydroisoxazol-5-ylmethyl,1,4-dioxan-2-ylmethyl, 2-morpholin-4-ylethyl, tetrahydro-2H-pyran-4-yl,and 1,3-oxazolidin-4-ylmethyl, wherein each of the oxetan-2-yl,oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl,tetrahydro-2H-pyran-4-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,4,5-dihydroisoxazol-5-yl, 1,4-dioxan-2-yl, morpholin-4-yl, and1,3-oxazolidin-4-yl, is each independently unsubstituted or substitutedwith 1, 2, 3, or 4 substituents selected from the group consisting ofalkyl (for example, methyl, ethyl), haloalkyl (e.g. trifluoromethyl),and oxo.

Another aspect of the invention relates to a group of compounds offormula (I), or pharmaceutically acceptable salts thereof, wherein R₁ isA-alkylene- and ring A is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl,each of which is optionally substituted as described in the Summary andin Detailed Description; R₂ is hydrogen, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl (for example, methyl, ethyl, propyl,tert-butyl), aryl (for example, optionally substituted phenyl), halo,haloalkyl (e.g. trifluoromethyl), or —(CR₂₁R₂₂)_(m)—OH; R₃ is hydrogen,alkyl (for example, methyl, ethyl, n-propyl, tert-butyl), alkylcarbonyl(e.g. acetyl), aryl (for example, optionally substituted phenyl),cycloalkyl (for example, cyclopropyl, cyclohexyl, each of which isoptionally substituted), halo, haloalkyl (e.g. trifluoromethyl),heterocycle (for example, morpholinyl), or —(CR₃₁R₃₂)_(m)—OH, and L₁,R₄, R₂₁, R₂₂, R₃₁, R₃₂, m, and the optional substituents of the aryl,cycloalkyl, and heterocycle moieties are as disclosed in the Summary andDetailed Description. For example R₁ is furanylmethyl, oxazolylmethyl,isoxazolylmethyl, or oxadiazolylmethyl, wherein each of the furanyl,oxazolyl, isoxazolyl and oxadiazolyl is optionally substituted with thegroup consisting of alkyl (e.g. methyl, ethyl), halo, and haloalkyl(e.g. trifluoromethyl).

For the preceding two groups of compounds of formula (I), R₂₁ and R₂₂are the same or different, and are each independently hydrogen, methyl,or ethyl. m, for example, is 1. R₃₁ and R₃₂ (R₃₁ and R₃₂ can be the sameor different) are, for example, alkyl (for example, methyl) or haloalkyl(for example, 2-iodoethyl, trifluoromethyl).

In one embodiment, R₃ is alkyl (for example, methyl, ethyl, n-propyl, ortert-butyl) or —(CR₃₁R₃₂)_(m)—OH, and R₂ is hydrogen or alkyl (forexample, methyl, ethyl, propyl, tert-butyl); wherein R₃₁, R₃₂ and m areas described in the Summary and in embodiments described hereina bove.Examples include those wherein R₂ is hydrogen or alkyl (for example,methyl), and R₃ is —(CR₃₁R₃₂)_(m)—OH wherein m is 1, and R₃₁ and R₃₂ arealkyl (such as, but not limited to, methyl) or haloalkyl (such as, butnot limited to, trifluoromethyl). Other examples include those whereinR₂ is hydrogen or alkyl (for example, methyl), and R₃ is alkyl (forexample, tert-butyl). Yet other examples include those wherein R₂ ishydrogen or alkyl (for example, methyl), and R₃ is —(CR₃₁R₃₂)_(m)—OH,wherein R₃₁ and R₃₂ are alkyl (for example, methyl), and m is 1.

Another aspect of the invention provides a group of compounds of formula(I), or pharmaceutically acceptable salts thereof, wherein R₁ is A orA-alkylene-, R₂ and R₃, together with the carbon atoms to which they areattached form a monocyclic ring, and A, R₄, L₁, and said monocyclic ringare as described in the Summary. Some examples of ring A are asdescribed herein above. Certain examples of the monocyclic ring formedby R₂, R₃, and the carbon atoms to which they are attached arerepresented by formulae (viii), (ix), (ixa), and (xi)-(xxix), each ofwhich is optionally substituted with substituents as described in theSummary and in the Detailed Description, and each of which is optionallyfused with benzo or oxadiazole. One example of such fused ring isrepresented by formula (x) or (xa). Examples of the optionalsubstituents on the rings formed by R₂, R₃, and the carbon atoms towhich they are attached include, but are not limited to, alkyl such asC₁₋₆ alkyl, hydroxy, and oxo.

Yet another aspect of the invention relates to a group of compounds offormula (I) or pharmaceutically acceptable salts thereof, wherein R₁ isalkoxyalkyl (e.g. 2-ethoxyethyl, 2-methoxymethyl,2-methoxy2-methylpropyl, 3-methoxypropyl), alkoxyalkoxyalkyl (e.g.2-(2-methoxyethoxy)ethyl), or hydroxyalkyl (e.g.3-hydroxy-3-methylbutyl), R₂ and R₃, together with the carbon atoms towhich they are attached, form a 4-, 5-, 6-, or 7-membered monocyclicring, optionally fused to benzo or oxadiazole, said monocyclic ringcontains zero or one additional double bond, zero oxygen atom and zeronitrogen atom as ring atoms; two non-adjacent atoms of said monocyclicring are linked by an alkenylene bridge of 2, 3, or 4 carbon atoms, orlinked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, saidmonocyclic ring is independently unsubstituted or substituted with 1, 2,3, 4, or 5 substituents independently selected from the group consistingof oxo, alkyl, halo, —OH, —O(alkyl), and haloalkyl; two substituents onthe same carbon atom of said monocyclic ring, together with the carbonatom to which they are attached, optionally form a 3-, 4-, 5-, or6-membered monocyclic cycloalkyl ring, wherein the monocyclic cycloalkylring is optionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from the group consisting of alkyl and haloalkyl;and R₄ and L₁ are as described in the Summary and Detailed Description.Some examples of the ring formed by R₂, R₃, and the carbon atoms towhich they are attached are represented by formulae (xii), (xiii) and(xiv), each of which is optionally substituted as described in theSummary. Examples of the optional substituents include, but are notlimited to, alkyl such as C₁₋₆ alkyl (e.g. methyl), hydroxy, and oxo.

A further aspect of the invention provides a group of compounds offormula (I) or pharmaceutically acceptable salts thereof, wherein R₁ isalkoxyalkyl (e.g. 2-ethoxyethyl, 2-methoxymethyl,2-methoxy2-methylpropyl, 3-methoxypropyl), alkoxyalkoxyalkyl (e.g.2-(2-methoxyethoxy)ethyl), or hydroxyalkyl (e.g.3-hydroxy-3-methylbutyl), R₂ and R₃, together with the carbon atoms towhich they are attached, form a 4-, 5-, 6-, or 7-membered monocyclicring optionally fused to benzo or oxadiazole, containing zero or oneadditional double bond, and one oxygen atom, and zero or one nitrogenatom as ring atoms; and R₄ and L₁ are as described in the Summary andDetailed Description. Some examples of the monocyclic ring formed by R₂,R₃, and the carbon atoms to which they are attached are represented byformula (xv)-(xxix), each of which is optionally substituted asdescribed in the Summary and Detailed Description. In one embodiment,the ring formed by R₂, R₃, and the carbon atoms to which they areattached are represented by formula (xv), (xviii), or (xxix), each ofwhich is optionally substituted as described in the Summary and DetailedDescription. Examples of the optional substituents of these ringsinclude, but are not limited to, alkyl such as C₁₋₆ alkyl (e.g. methyl),hydroxy, and oxo.

Yet a further aspect of the invention provides a group of compounds offormula (I) or pharmaceutically acceptable salts thereof, wherein R₁ isalkoxyalkyl (e.g. 2-ethoxyethyl, 2-methoxymethyl,2-methoxy2-methylpropyl, 3-methoxypropyl), alkoxyalkoxyalkyl (e.g.2-(2-methoxyethoxy)ethyl), or hydroxyalkyl (e.g.3-hydroxy-3-methylbutyl), and R₂ and R₃, together with the carbon atomto which they are attached, form a ring as represented by formula (x) or(xa), and R₄, L₁, and the optional substituents of formula (x) and (xa)are as described in the Summary and in the Detailed Description.

Within each group of compounds of formula (I) as described in thepreceding paragraphs, L₁ and R₄ have values as described in the Summaryand the Detailed Description.

Thus, within each group of the compounds as described in the precedingparagraphs, examples of a subgroup include those wherein R₄ is aryl(e.g. phenyl, naphthyl, 1,2-dihydroacenaphthylenyl), heteroaryl (forexample, quinolinyl, isoquinolinyl, benzofuranyl, thienyl, pyrazolyl,pyridinyl), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, spiro[2.5]octane), heterocycle(tetrahydropyranyl, dihydropyranyl, 2,3-dihydrobenzofuranyl,1,3-benzodioxolyl), arylalkyl, heteroarylalkyl (e.g.3-thien-2-ylpropyl), heterocyclealkyl (for example,tetrahydro-2H-pyranylmethyl), cycloalkylalkyl (e.g. cyclopentylmethyl,cyclohexylmethyl), R₉-L₂-R₁₀, alkynyl, or alkyl, wherein the alkyl groupis optionally substituted with R_(e)R_(f)N—, —OH, or alkoxycarbonyl,wherein R₉, L₂, R₁₀, R_(e) and R_(f), and the optional substituents ofthe aryl, heteroaryl, cycloalkyl, and heterocycle moieties are asdescribed in the Summary and in the Detailed Description.

Examples of another subgroup of compounds of formula (I) include thosewherein L₁ is a bond, and R₄ is aryl (e.g. phenyl, naphthyl,1,2-dihydroacenaphthylenyl), heteroaryl (for example, quinolinyl,isoquinolinyl, benzofuranyl, thienyl, pyrazolyl, pyridinyl), cycloalkyl(e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,spiro[2.5]octane), heterocycle (tetrahydropyranyl, dihydropyranyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl), arylalkyl, heteroarylalkyl(e.g. 3-thien-2-ylpropyl), heterocyclealkyl (for example,tetrahydro-2H-pyranylmethyl), cycloalkylalkyl (e.g. cyclopentylmethyl,cyclohexylmethyl), R₉-L₂-R₁₀, alkynyl, or alkyl, wherein the alkyl groupis optionally substituted with R_(e)R_(f)N—, —OH, or alkoxycarbonyl,wherein R₉, L₂, R₁₀, R_(e) and R_(f), and the optional substituents ofthe aryl, heteroaryl, cycloalkyl, and heterocycle moieties are asdescribed in the Summary and in the Detailed Description.

Other examples of a subgroup include those wherein L₁ is a bond, and R₄is optionally substituted phenyl or R₁₀-L₂-R₉—, wherein R₉ is aryl (forexample, phenyl, naphthyl) or heteroaryl (e.g. pyrazolyl), L₂ isalkylene (e.g. CH₂, CH₂CH₂), and R₁₀ is as described in the Summary. Forexample, R₁₀ is heterocycle (e.g. tetrahydrofuranyl, azetidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl) or aryl (e.g.phenyl); wherein the phenyl, aryl, heteroaryl, and heterocycle moietiesof R₄, R₉, and R₁₀ are each optionally substituted as described in theSummary and the Detailed Description.

Other examples of a subgroup include those wherein L₁ is a bond, and R₄is optionally substituted phenyl or R₁₀-L₂-R₉—, wherein R₉ is aryl (forexample, phenyl, naphthyl) or heteroaryl (e.g. pyrazolyl), L₂ is O, andR₁₀ is as described in the Summary. for example, R₁₀ is cycloalkyl(cyclopropyl), cycloalkylalkyl (e.g. cyclopropylmethyl,cyclopentylmethyl), or heterocycle (e.g. tetrahydrofuranyl, azetidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl); wherein thephenyl, aryl, heteroaryl, cycloalkyl, and heterocycle moieties of R₄,R₉, and R₁₀ are each optionally substituted as described in the Summaryand the Detailed Description.

In certain embodiments of the subgroups described above, R₉ isoptionally aryl (for example, phenyl), optionally further substituted asdescribed in the Summary and in the Detailed Description.

Examples of another subgroup of compounds of formula (I) include thosewherein L₁ is NR_(g), and R₄ is arylalkyl, cycloalkyl, cycloalkylalkyl,or alkyl, wherein the alkyl group is optionally substituted withR_(e)R_(f)N—, —OH, or alkoxycarbonyl, and R_(e), R_(g), and R_(f), andthe optional substituents of the aryl and cycloalkyl moieties are asdescribed in the Summary and in the Detailed Description.

Yet a further aspect of the invention provides compounds of formula (II)or pharmaceutically acceptable salts thereof,

wherein

R_(1a) is alkoxyalkyl, hydroxyalkyl, alkyl, haloalkyl, orcycloalkylalkyl wherein the cycloalkyl moiety is optionally substitutedwith 1, 2, 3, 4, 5, or 6 substituents independently selected from thegroup consisting of oxo, alkyl, halo, —OH, —O(alkyl), and haloalkyl;

R_(2a) is hydrogen or alkyl;

R_(x) is an optional substituent of phenyl, selected from the groupconsisting of alkyl, alkylcarbonyl, alkoxy, alkoxyalkoxy, cyano, formyl,halogen, haloalkoxy, hydroxy, hydroxyalkyl, haloalkyl, ═N—OH,NZ_(1a)Z_(2a)—(CR^(41a)R_(42a))_(v)—O—, —O—(CR_(41a)R_(42a))_(v)-G_(1a),—(CR_(41a)R_(42a))_(v)-G_(1a), —(CR_(41a)R_(42a))_(v)—NZ_(1a)Z_(2a), andNZ_(1a)Z_(2a);

G_(1a) is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containingone nitrogen atom and optionally 1 or 2 additional heteroatom in thering, wherein said ring is attached to the parent moiety through thenitrogen atom, and said ring is optionally substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, ═N—CN, ═N—OR_(51a), —CN, oxo, —OR_(51a),—OC(O)R_(51a), —OC(O)N(R_(51a))₂, —S(O)₂R_(52a), —S(O)₂N(R_(51a))₂,—C(O)R_(51a), —C(O)OR_(51a), —C(O)N(R_(51a))₂, —N(R_(51a))₂,—N(R_(51a))C(O)R_(51a), —N(R_(51a))S(O)₂R_(52a),—N(R_(51a))C(O)O(R_(52a)), —N(R_(51a))C(O)N(R_(51a))₂,—(CR_(1e)R_(1f))_(w)—OR₅₁, —(CR_(1e)R_(1f))_(w)—OC(O)R_(51a),—(CR_(1e)R_(1f))_(w)—OC(O)N(R_(51a))₂,—(CR_(1e)R_(1f))_(w)—S(O)₂R_(52a),—(CR_(1e)R_(1f))_(w)—S(O)₂N(R_(51a))₂, —(CR_(1e)R_(1f))_(w)—C(O)R_(51a),—(CR_(1e)R_(1f))_(w)—C(O)OR_(51a), —(CR_(1e)R_(1f))_(w)—C(O)N(R_(51a))₂,—(CR_(1e)R_(1f))_(w)—N(R_(51a))₂,—(CR_(1e)R_(1f))_(w)—N(R_(51a))C(O)R_(51a),—(CR_(1e)R_(1f))_(w)—N(R_(51a))S(O)₂R_(52a),—(CR_(1e)R_(1f))_(w)—N(R_(51a))C(O)O(R_(52a)),—(CR_(1e)R_(1f))_(w)—N(R_(51a))C(O)N(R_(51a))₂, and—(CR_(1e)R_(1f))_(w)—CN;

R_(51a), at each occurrence, is independently hydrogen, C₁-C₄ alkyl,C₁-C₄ haloalkyl, —(CR_(2e)R_(2f))_(y)—OR⁵³, monocyclic cycloalkyl, or—(CR_(2e)R_(2f))_(y)-(monocyclic cycloalkyl); wherein R_(53a) ishydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, monocyclic cycloalkyl, or—(CR_(2a)R_(2f))_(y)-(monocyclic cycloalkyl);

R_(52a), at each occurrence, is independently C₁-C₄ alkyl, C₁-C₄haloalkyl, monocyclic cycloalkyl, or —(CR_(2e)R_(2f))_(y)-(monocycliccycloalkyl);

the monocyclic cycloalkyl moiety, as a substituent, or as part of asubstituent, as represented by R_(41a), R_(52a), and R_(53a) are eachindependently unsubstituted or substituted with 1, 2, 3, or 4substituents selected from the group consisting of C₁-C₄ alkyl, halo,hydroxy, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl;

R_(41a), R_(42a), R_(1e), R_(1f), R_(2e), and R_(2f), at eachoccurrence, are each independently hydrogen, alkyl, haloalkyl, or halo;

v, w, and y, at each occurrence, are each independently 1, 2, 3, or 4;

Z_(1a) and Z_(2a) are each independently hydrogen, alkyl, alkoxyalkyl,alkylcarbonyl, cyanoalkyl, haloalkyl, or formyl; and

n is 1, 2, 3, 4, or 5.

In compounds of formula (II), R_(2a) is hydrogen or alkyl such as C₁₋₆alkyl. In one embodiment, R_(2a) is hydrogen. In another embodiment,R_(2a) is C₁₋₆ alkyl such as, but not limited to, methyl, or tert-butyl.Examples of R_(1a) include, but are not limited to, cycloalkylalkylwherein the cycloalkyl moiety include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which isindependently unsubstituted or substituted as described in the Summary.One example of the cycloalkyl moiety is cyclobutyl. Examples of theoptional substituents of the cycloalkyl moiety include, but are notlimited to, alkyl, haloalkyl, hydroxy, oxo, alkoxy, and haloalkoxy. Inother embodiments, R_(1a) is alkyl (such as, but not limited to, butyl).In yet another embodiment, R_(1a) is halolakyl. In a further embodiment,R_(1a), for example, is alkoxyalkyl (for example, 2-methoxyethyl).

Compounds of the present invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The presentinvention contemplates various stereoisomers (including enantiomers anddiastereomers) and mixtures of various ratio thereof and are includedwithin the scope of this invention. Individual stereoisomers ofcompounds of the present invention may be prepared synthetically fromcommercially available starting materials containing asymmetric orchiral centers or by preparation of racemic mixtures followed byresolution well known to those of ordinary skill in the art. Thesemethods of resolution are exemplified by (1) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography and liberationof the optically pure product from the auxiliary or (2) directseparation of the mixture of optical enantiomers on chiralchromatographic columns.

Geometric isomers can exist in the present compounds. The inventioncontemplates the various geometric isomers and mixtures thereofresulting from the disposition of substituents around a carbon-carbondouble bond, a carbon-nitrogen double bond, a cycloalkyl group, or aheterocycle group. Substituents around a carbon-carbon double bond or acarbon-nitrogen double bond are designated as being of Z or Econfiguration; and substituents around a cycloalkyl or heterocycle aredesignated as being of cis or trans configuration.

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism.

The formulae drawings within this specification can represent only oneof the possible tautomeric or stereoisomeric forms. It is to beunderstood that the invention encompasses any tautomeric orstereoisomeric form, and mixtures thereof, and is not to be limitedmerely to any one tautomeric or stereoisomeric form utilized within thenaming of the compounds or formulae drawings.

c. BIOLOGICAL DATA

(i) In Vitro Methods—Human CB₂ and CB₁ Radioligand Binding Assays:

The CB₁ and CB₂ radioligand binding assays described herein are utilizedto determine the selectivity of compounds of the present invention forbinding to CB₂ relative to CB₁ receptors.

HEK293 cells stably expressing human CB₂ receptors were grown until aconfluent monolayer was formed. Briefly, the cells were harvested andhomogenized in TE buffer (50 mM Tris-HCl, 1 mM MgCl₂, and 1 mM EDTA)using a polytron for 2×10 second bursts in the presence of proteaseinhibitors, followed by centrifugation at 45,000×g for 20 minutes. Thefinal membrane pellet was re-homogenized in storage buffer (50 mMTris-HCl, 1 mM MgCl₂, and 1 mM EDTA and 10% sucrose) and frozen at −78°C. until used. Saturation binding reactions were initiated by theaddition of membrane preparation (protein concentration of 5 μg/well forhuman CB₂) into wells of a deep well plate containing ([³H]CP-55,940(120 Ci/mmol, a nonselective CB agonist commercially available fromTocris) in assay buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl₂, and 0.5mg/mL fatty acid free BSA, pH 7.4). After 90 min incubation at 30° C.,binding reaction was terminated by the addition of 300 μl/well of coldassay buffer followed by rapid vacuum filtration through a UniFilter-96GF/C filter plates (pre-soaked in 1 mg/mL BSA for 2 hours). The boundactivity was counted in a TopCount using Microscint-20. Saturationexperiments were conducted with twelve concentrations of [³H]CP-55,940ranging from 0.01 to 8 nM. Competition experiments were conducted with0.5 nM [³H]CP-55,940 and five concentrations of displacing ligandsselected from the range of 0.01 nM to 10 μM. The addition of 10 μMunlabeled CP-55,940 (Tocris, Ellisville, Mo.) was used to assessnonspecific binding.

HEK293 cells stably expressing rat CB₂ receptors were grown until aconfluent monolayer was formed. Briefly, the cells were harvested andhomogenized in TE buffer (50 mM Tris-HCl, 1 mM MgCl₂, and 1 mM EDTA)using a polytron for 2×10 second bursts in the presence of proteaseinhibitors, followed by centrifugation at 45,000×g for 20 minutes. Thefinal membrane pellet was re-homogenized in storage buffer (50 mMTris-HCl, 1 mM MgCl₂, and 1 mM EDTA and 10% sucrose) and frozen at −78°C. until used. Saturation binding reactions were initiated by theaddition of membrane preparation (protein concentration of 20 μg/wellfor rat CB₂) into wells of a deep well plate containing [³H]CP-55,940(120 Ci/mmol, a nonselective CB agonist commercially available fromTocris) in assay buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl₂, and 0.5mg/mL fatty acid free BSA, pH 7.4). After 45 min incubation at 30° C.,binding reaction was terminated by the addition of 300 μl/well of coldassay buffer followed by rapid vacuum filtration through a UniFilter-96GF/C filter plates (pre-soaked in 1 mg/mL BSA for 2 hours). The boundactivity was counted in a TopCount using Microscint-20. Saturationexperiments were conducted with twelve concentrations of [³H]CP-55,940ranging from 0.01 to 8 nM. Competition experiments were conducted with0.5 nM [³H]CP-55,940 and five concentrations of displacing ligandsselected from the range of 0.01 nM to 10 μM. The addition of 10 μMunlabeled CP-55,940 (Tocris, Ellisville, Mo.) was used to assessnonspecific binding.

Representative compounds of the present invention bound to CB₂ receptorswith a K_(i) of less than about 1,000 nM, preferably less than 400 nM,more preferably less than 200 nM and, most preferably lower than 100 nM.

HEK293 human CB₁ membranes were purchased from Perkin Elmer. Binding wasinitiated by the addition of membranes (8-12 μg per well) into wells(Scienceware 96-well DeepWell plate, VWR, West Chester, Pa.) containing[³H]CP-55,940 (120 Ci/mmol, Perkin Elmer, Boston, Mass.) and asufficient volume of assay buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl₂,and 0.5 mg/mL fatty acid free BSA, pH 7.4) to bring the total volume to250 μL. After incubation (30° C. for 90 minutes), binding was terminatedby the addition of 300 μL per well of cold assay buffer and rapid vacuumfiltration (FilterMate Cell Harvester, Perkin Elmer, Boston, Mass.)through a UniFilter-96 GF/C filter plate (Perkin Elmer, Boston, Mass.)(pre-soaked in 0.3% PEI at least 3 hours), followed by five washes withcold assay buffer. The bound activity was counted in the TopCount usingMicroscint-20 (both from Perkin Elmer, Boston, Mass.). Competitionexperiments were conducted with 1 nM [³H]CP-55,940 and fiveconcentrations (1 nM to 10 μM) of displacing ligands. The addition of 10unlabeled CP-55,940 (Tocris, Ellisville, Mo.) was used to assessnonspecific binding. Representative compounds of the present inventionbound to CB₁ receptors with K₁ of about 10 fold to about 1000 fold ormore higher than that for CB₂ receptors. These results show that thecompounds of the present invention preferably bind to CB₂ receptors,therefore are selective ligands for the CB₂ receptor.

(ii) In Vivo Data:

Animals

Adult male Sprague-Dawley rats (250-300 g body weight, Charles RiverLaboratories, Portage, Mich.) are used. Animal handling and experimentalprotocols are approved by the Institutional Animal Care and UseCommittee (IACUC) at Abbott Laboratories. For all surgical procedures,animals are maintained under isoflurane anesthesia (4-5% to induce, 1-3%to maintain), and the incision sites are sterilized using a 10%povidone-iodine solution prior to and after surgeries.

Incisional Model of Postoperative Pain

A skin incision model of postoperative pain can be produced using theprocedures described in Brennan et al., 1996, Pain, 64, 493. All ratsare anesthetized with isoflurane delivered via a nose cone. Right hindpaw incision is performed following sterilization procedures. Theplantar aspect of the left hind paw is placed through a hole in asterile plastic drape. A 1-cm longitudinal incision is made through theskin and fascia of the plantar aspect of the hind paw, starting 0.5 cmfrom the proximal edge of the heel and extending towards the toes, theplantar muscle is elevated and incised longitudinally leaving the muscleorigin and insertion points intact. The skin is then closed with twomattress sutures (5-0 nylon). After surgery, animals are then allowed torecover for 2 hours, at which time tactile allodynia is assessed asdescribed below. To evaluate the anti-nociceptive effects, animals arei.p. administered vehicle or test compound 90 minutes following skinincision and tactile allodynia is assessed 30 minutes after compoundadministration.

Tactile allodynia can be measured using calibrated von Frey filaments(Stoelting, Wood Dale, Ill.) as described in Chaplan, S. R., F. W. Bach,J. W. Pogrel, J. M. Chung and T. L. Yaksh, 1994, Quantitative Assessmentof Tactile Allodynia in the Rat Paw, J. Neurosci. Methods, 53, 55. Ratsare placed into inverted individual plastic cage (20×12.5×20 cm) on topof a suspended wire mesh grid, and are acclimated to the test chambersfor 20 minutes. The von Frey filaments are applied perpendicularly fromunderneath the cage through openings in the wire mesh floor directly toan area within 1-3 mm (immediately adjacent) of the incision, and thenheld in this position for approximately 8 seconds with enough force tocause a slight bend in the filament. Positive responses include anabrupt withdrawal of the hind paw from the stimulus, or flinchingbehavior immediately following removal of the stimulus. A 50% withdrawalthreshold can be determined using an up-down procedure (Dixon, W. J.,1980, Efficient Analysis of Experimental Observations, Ann. Rev.Pharmacol. Toxicol., 20, 441).

Representative compounds of the present invention showed efficacy atless than about 300 micromoles/kg in the skin incision model ofpostoperative pain. In a more preferred embodiment, compounds describedherein showed efficacy at less than about 100 micromoles/kg in the skinincision model of postoperative pain.

Complete Freund's Adjuvant (CFA) Model of Inflammatory Pain

Chronic inflammatory thermal hyperalgesia was induced by injection of150 μL of a 50% solution of CFA in phosphate buffered saline (PBS) intothe plantar surface of the right hind paw in rats; control animalsreceived only PBS treatment. Thermal hyperalgesia was assessed 48 hourspost CFA injection. Thermal hyperalgesia was determined using acommercially available thermal paw stimulator (University AnesthesiologyResearch and Development Group (UARDG), University of California, SanDiego, Calif.) described by Hargreaves et al. (Hargreaves, et. al.,1988, Pain 32, 77). Rats were placed into individual plastic cubiclesmounted on a glass surface maintained at 30° C., and allowed a 20 minhabituation period. A thermal stimulus, in the form of radiant heatemitted from a focused projection bulb, was then applied to the plantarsurface of each hind paw. The stimulus current was maintained at4.50±0.05 amp, and the maximum time of exposure was set at 20.48 sec tolimit possible tissue damage. The elapsed time until a brisk withdrawalof the hind paw from the thermal stimulus was recorded automaticallyusing photodiode motion sensors. The right and left hind paw of each ratwas tested in three sequential trials at approximately 5-minuteintervals. Paw withdrawal latency (PWL) was calculated as the mean ofthe two shortest latencies.

Representative compounds of the present invention showed a statisticallysignificant change in paw withdrawal latency versus a saline vehicle atless than about 300 micromoles/kg in the Complete Freund's Adjuvant(CFA) model of inflammatory pain.

Spinal Nerve Ligation Model of Neuropathic Pain

A model of spinal nerve ligation-induced (SNL model) neuropathic painwas produced using the procedure originally described in Kim, S. H. andJ. M. Chung, 1992, An experimental model for peripheral neuropathyproduced by segmental spinal nerve ligation in the rat, Pain, 50, 355.The left L5 and L6 spinal nerves of the rat were isolated adjacent tothe vertebral column and tightly ligated with a 5-0 silk suture distalto the DRG, and care was taken to avoid injury of the L4 spinal nerve.Sham rats underwent the same procedure, but without nerve ligation. Allanimals were allowed to recover for at least one week and not more thanthree weeks prior to assessment of tactile allodynia.

Tactile allodynia was measured using calibrated von Frey filaments(Stoelting, Wood Dale, Ill.) as described in Chaplan, S. R., F. W. Bach,J. W. Porgrel, J. M. Chung and T. L. Yaksh, 1994, Quantitativeassessment of tactile allodynia in the rat paw, J. Neurosci. Methods,53, 55. Rats were placed into inverted individual plastic containers(20×12.5×20 cm) on top of a suspended wire mesh grid, and acclimated tothe test chambers for 20 minutes. The von Frey filaments were presentedperpendicularly to the plantar surface of the selected hind paw, andthen held in this position for approximately 8 sec with enough force tocause a slight bend in the filament. Positive responses included anabrupt withdrawal of the hind paw from the stimulus, or flinchingbehavior immediately following removal of the stimulus. A 50% withdrawalthreshold was determined using an up-down procedure as described inDixon, W. J., 1980, Efficient analysis of experimental observations,Ann. Rev. Pharmacol. Toxicol., 20, 441). Only rats with a baselinethreshold score of less that 4.25 g were used in this study, and animalsdemonstrating motor deficit were excluded. Tactile allodynia thresholdswere also assessed in several control groups, including naive,sham-operated, and saline infused animals a well as in the contralateralpaws of nerve-injured rats.

Representative compounds of the present invention showed efficacy atless than about 300 micromoles/kg in the spinal nerve ligation model ofneuropathic pain. In a more preferred embodiment, representativecompounds of the present invention showed efficacy at less than about100 micromoles/kg in the spinal nerve ligation model of neuropathicpain.

Capsaicin-Induced Secondary Mechanical Hypersensitivity:

Rats were allowed to acclimate to the study room for 1 hour. They werethen briefly restrained, and capsaicin was administered at 10 μg in 10μL of vehicle (10% ethanol and 2-hydroxypropyl cyclodextrin) byintraplantar injection into the center of the right hind paw. Secondarymechanical hyperalgesia was measured at the heel away from the site ofinjection at 180 min following capsaicin (Joshi et al 2006, Neuroscience143, 587-596). Compounds are injected (i.p.) 30 min before testing (150min post-capsaicin).

Tactile allodynia was measured as described above.

Representative compounds of the present invention showed a statisticallysignificant change in paw withdrawal latency versus a saline vehicle atless than about 300 micromoles/kg. In a more preferred embodiment,representative compounds of the present invention showed efficacy atless than about 50 micromoles/kg.

MIA-Induced Knee Joint Osteoarthritic Pain Model

Unilateral knee joint osteoarthritis was induced in the rats by a singleintra-articular (i.a.) injection of sodium monoiodoacetate (MIA, 3 mg in0.05 mL sterile isotonic saline) into the right knee joint cavity underlight isoflurane anesthesia using a 26G needle. The dose of the MIA (3mg/i.a. injection) was selected based on results obtained frompreliminary studies wherein an optimal pain behavior was observed atthis dose. Pain behavioral assessment of hind limb grip force wereconducted by recording the maximum compressive force exerted on the hindlimb strain gauge setup, in a commercially available grip forcemeasurement system (Columbus Instruments, Columbus, Ohio). The gripforce data was converted to a maximum hindlimb cumulative compressiveforce (CFmax) (gram force)/kg body weight for each animal. The analgesiceffects of test compounds were determined 20 days following the i.a.injection of MIA. The vehicle control group for each compound beingtested was assigned 0% whereas the age matched naïve group was assignedas being 100% (normal). The % effects for each dose group was thenexpressed as % return to normalcy compared to the naïve group. Compoundswere administered either orally (p.o.) or intraperitoneally (i.p.). Theassessment of the analgesic effects of test compounds is typically madeanytime between about 1 hour and about 5 hours following oraladministration. The assessment of the analgesic effects of testcompounds is typically made anytime between about 0.5 hour and about 2hours following i.p. administration. Selection of the preferred timepoints for measuring the analgesic effects of test compounds was basedupon consideration of the individual pharmacokinetic characteristics oftest compounds in the rat. Time points that were known or expected toprovide higher plasma concentrations of test compounds were preferredover those that were known or expected to provide lower concentrations.The assessment of the analgesic effects of test compounds can be madefollowing a single dose or following repeated dosing of test compoundswherein the frequency of dosing is 1 to 2 times daily. The duration ofsuch repeated daily dosing may last for any time greater than or equalto one day. A typical duration of repeated daily dosing is about 5 daysto about 12 days.

Representative compounds of the present invention showed a statisticallysignificant change in hind limb grip force strength versus a salinevehicle at less than about 300 micromoles/kg in the MIA model ofosteoarthritic pain following a single dose. In a more preferredembodiment, representative compounds of the present invention showed astatistically significant change in hind limb grip force strength versusa saline vehicle at less than about 50 micromoles/kg in the MIA model ofosteoarthritic pain following a single dose.

d. METHODS OF USING THE COMPOUNDS

The data contained herein above demonstrates that compounds of thepresent invention bind to the CB₂ receptor. Certain compounds of thepresent invention were shown to have an analgesic effect in two types ofanimal pain models relating to neuropathic and nociceptive pain.

One embodiment of the present invention provides a method for treatingpain (for example, neuropathic pain or nociceptive pain) in a mammal(including human) in need of such treatment. The method comprisesadministering to the mammal a therapeutically effective amount of any ofthe compounds described herein, or a pharmaceutically acceptable saltthereof, alone or in combination with one or more pharmaceuticallyacceptable carriers. The method further comprises administration ofcompounds of the invention as a single dose. The method also comprisesrepeated or chronic administration of compounds of the invention over aperiod of days, weeks, months, or longer. In certain embodiments, themethod comprises administering to the mammal a therapeutically effectiveamount of any of the compounds as described herein, or apharmaceutically acceptable salt thereof, in combination with one ormore nonsteroidal anti-inflammatory drug (NSAID), or with otheranalgesic agent (e.g. acetaminophen), or a combination thereof

Another embodiment of the present invention provides a method fortreating a disorder selected from the group consisting of inflammatorydisorders, immune disorders, neurological disorders, cancers of theimmune system, respiratory disorders, and cardiovascular disorders in amammal (including human) in need of such treatment. The method comprisesadministering to the mammal a therapeutically effective amount of any ofthe compounds described herein or a pharmaceutically acceptable saltthereof, alone or in combination with one or more pharmaceuticallyacceptable carriers.

Yet another embodiment of the present invention relates to a method forproviding neuroprotection in a mammal (including human) in need of suchtreatment. The method comprises administering to the mammal atherapeutically effective amount of any of the compounds describedherein or a pharmaceutically acceptable salt thereof, alone or incombination with one or more pharmaceutically acceptable carriers.

Another embodiment of the present invention provides a method ofincreasing the therapeutic effectiveness or potency of compounds of theinvention by repeated or chronic administration over a period of days,weeks, or months.

In addition to the data contained herein, several lines of evidencesupport the assertion that CB₂ receptors play a role in analgesia.HU-308 is one of the first highly selective CB₂ agonists identified thatelicits an antinociceptive response in the rat formalin model ofpersistent pain (Halms, L., et al., Proc. Nat. Acad. Sci., 1999, 96,14228-14233). The CB₂-selective cannabiniod ligand AM-1241 exhibitsrobust analgesic efficacy in animal models of acute thermal pain (Malan,T. P., et al., Pain, 2001, 93, 239-245; Ibrahim, M. M., et al., Proc.Nat. Acad. Sci., 2005, 102(8), 3093-3098), persistent pain (Hohmann, A.G., et al., J. Pharmacol. Exp. Ther., 2004, 308, 446-453), inflammatorypain (Nackley, A. G., et al., Neuroscience, 2003, 119, 747-757;Quartilho, A. et al., Anesthesiology, 2003, 99, 955-60), and neuropathicpain (Ibrahim, M. M., et al., Proc. Nat. Acad. Sci., 2003, 100,10529-10533). The CB₂-selective partial agonist GW405833, also known asL768242, is efficacious in rodent models of neuropathic, incisional, andboth chronic and acute inflammatory pain (Valenzano, K. J., et al.,Neuropharmacology, 2005, 48, 658-672 and Clayton, N., et al., Pain,2002, 96, 253-260).

The potential exists for CB₂ modulators to have opioid sparing effects.A synergy between the analgesic effects of morphine and the nonselectiveCB agonist Δ⁹-THC has been documented (Cichewicz, D. L., Life Sci. 2004,74, 1317-1324). Therefore, CB₂ ligands have additive or synergisticanalgesic effects when used in combination with lower doses of morphineor other opioids, providing a strategy for reducing adverse opioidevents, such as tolerance, constipation, and respiratory depression,without sacrificing analgesic efficacy.

CB₂ receptors are present in tissues and cell types associated withimmune functions and CB₂ receptor mRNA is expressed by human B cells,natural killer cells, monocytes, neutrophils, and T cells (Galiegue etal., Eur. J. Biochem., 1995, 232, 54-61). Studies with CB₂ knockout micehave suggested a role for CB₂ receptors in modulating the immune system(Buckley, N. E., et al., Eur. J. Pharmacol. 2000, 396, 141-149).Although immune cell development and differentiation are similar inknockout and wild type animals, the immunosuppressive effects of Δ⁹-THCare absent in the CB₂ receptor knockout mice, providing evidence for theinvolvement of CB₂ receptors in immunomodulation. As such, selective CB₂modulators may be useful for the treatment of autoimmune diseasesincluding but not limited to multiple sclerosis, rheumatoid arthritis,systemic lupus, myasthenia gravis, type I diabetes, irritable bowelsyndrome, psoriasis, psoriatic arthritis, and hepatitis; and immunerelated disorders including but not limited to tissue rejection in organtransplants, gluten-sensitive enteropathy (Celiac disease), asthma,chronic obstructive pulmonary disease, emphysema, bronchitis, acuterespiratory distress syndrome, allergies, allergic rhinitis, dermatitis,and Sjogren's syndrome.

Microglial cells are considered to be the immune cells of the centralnervous system (CNS) where they regulate the initiation and progressionof immune responses. CB₂ receptor expression on microglia is dependentupon inflammatory state with higher levels of CB₂ found in primed,proliferating, and migrating microglia relative to resting or fullyactivated microglial (Carlisle, S. J., et al. Int. Immunopharmacol.,2002, 2, 69). Neuroinflammation induces many changes in microglia cellmorphology and there is an upregulation of CB₂ receptors and othercomponents of the endocannabinoid system.—Neuroinflammation occurs inseveral neurodegenerative diseases, and induction of microglial CB₂receptors has been observed (Carrier, E. J., et al., Current DrugTargets—CNS & Neurological Disorders, 2005, 4, 657-665). Thus, CB₂ligands may be clinically useful for the treatment of neuroinflammation.

Multiple sclerosis is common immune-mediated disease of the CNS in whichthe ability of neurons to conduct impulses becomes impaired throughdemyelination and axonal damage. The demyelination occurs as aconsequence of chronic inflammation and ultimately leads to a broadrange of clinical symptoms that fluctuate unpredictably and generallyworsen with age. These include painful muscle spasms, tremor, ataxia,motor weakness, sphincter dysfunction, and difficulty speaking (Pertwee,R. G., Pharmacol. Ther. 2002, 95, 165-174). The CB₂ receptor isup-regulated on activated microglial cells during experimentalautoimmune encephalomyelitis (EAE) (Maresz, K., et al., J. Neurochem.2005, 95, 437-445). CB₂ receptor activation prevents the recruitment ofinflammatory cells such as leukocytes into the CNS (Ni, X., et al.,Multiple Sclerosis, 2004, 10, 158-164) and plays a protective role inexperimental, progressive demyelination (Arevalo-Martin, A.; et al., J.Neurosci., 2003, 23(7), 2511-2516), which are critical features in thedevelopment of multiple sclerosis. Thus, CB₂ receptor modulators mayprovide a unique treatment for demyelinating pathologies.

Alzheimer's disease is a chronic neurodegenerative disorder accountingfor the most common form of elderly dementia. Recent studies haverevealed that CB₂ receptor expression is upregulated in neuriticplaque-associated microglia from brains of Alzheimer's disease patients(Benito, C., et al., J. Neurosci., 2003, 23(35), 11136-11141). In vitro,treatment with the CB₂ agonist JWH-133 abrogated □-amyloid-inducedmicroglial activation and neurotoxicity, effects that can be blocked bythe CB₂ antagonist SR144528 (Ramirez, B. G., et al., J. Neurosci. 2005,25(8), 1904-1913). CB₂ modulators may possess both anti-inflammatory andneuroprotective actions and thus have clinical utility in treatingneuroinflammation and in providing neuroprotection associated with thedevelopment of Alzheimer's disease.

Increased levels of epithelial CB₂ receptor expression are observed inhuman inflammatory bowel disease tissue (Wright, K., et al.,Gastroenterology, 2005, 129, 437-453). Activation of CB₂ receptorsre-established normal gastrointestinal transit after endotoxicinflammation was induced in rats (Mathison, R., et al., Br. J.Pharmacol. 2004, 142, 1247-1254). CB₂ receptor activation in a humancolonic epithelial cell line inhibited TNF-□-induced interleukin-8(IL-8) release (Ihenetu, K. et al., Eur. J. Pharmacol. 2003, 458,207-215). Chemokines released from the epithelium, such as theneutrophil chemoattractant IL-8, are upregulated in inflammatory boweldisease (Warhurst, A. C., et al., Gut, 1998, 42, 208-213). Thus,administration of CB₂ receptor modulators may represent a novel approachfor the treatment of inflammation and disorders of the gastrointestinaltract including but not limited to inflammatory bowel disease, irritablebowel syndrome, secretory diarrhea, ulcerative colitis, Crohn's diseaseand gastroesophageal reflux disease (GERD).

Hepatic fibrosis occurs as a response to chronic liver injury andultimately leads to cirrhosis, which is a major worldwide health issuedue to the severe accompanying complications of portal hypertension,liver failure, and hepatocellular carcinoma (Lotersztajn, S., et al.,Annu. Rev. Pharmacol. Toxicol., 2005, 45, 605-628). Although CB₂receptors were not detectable in normal human liver, CB₂ receptors wereexpressed liver biopsy specimens from patients with cirrhosis.Activation of CB₂ receptors in cultured hepatic myofibroblasts producedpotent antifibrogenic effects (Julien, B., et al., Gastroenterology,2005, 128, 742-755). In addition, CB₂ knockout mice developed enhancedliver fibrosis after chronic administration of carbon tetrachloriderelative to wild-type mice. Administration of CB₂ receptor modulatorsmay represent a unique approach for the treatment of liver fibrosis.

Cough is a dominant and persistent symptom of many inflammatory lungdiseases, including asthma, chronic obstructive pulmonary disease, viralinfections, and pulmonary fibrosis (Patel, H. J., et al., Brit. J.Pharmacol., 2003, 140, 261-268). Recent studies have provided evidencefor the existence of neuronal CB₂ receptors in the airways, and havedemonstrated a role for CB₂ receptor activation in cough suppression(Patel, H. J., et al., Brit. J. Pharmacol., 2003, 140, 261-268 andYoshihara, S., et al., Am. J. Respir. Crit. Care Med., 2004, 170,941-946). Both exogenous and endogenous cannabinoid ligands inhibit theactivation of C-fibers via CB₂ receptors and reduce neurogenicinflammatory reactions in airway tissues (Yoshihara, S., et al., J.Pharmacol. Sci. 2005, 98(1), 77-82; Yoshihara, S., et al., Allergy andImmunology, 2005, 138, 80-87). Thus, CB₂-selective modulators may haveutility as antitussive agents for the treatment of pulmonaryinflammation, chronic cough, and a variety of airway inflammatorydiseases including but not limited to asthma, chronic obstructivepulmonary disease, and pulmonary fibrosis.

There is a substantial genetic contribution to bone mass density and theCB₂ receptor gene is associated with human osteoporosis (Karsak, M., etal., Human Molecular Genetics, 2005, 14(22), 3389-3396). Osteoclasts andosteoblasts are largely responsible for maintaining bone structure andfunction through a process called remodeling, which involves resorptionand synthesis of bone (Boyle, W. J., et al., Nature, 2003, 423,337-342). CB₂ receptor expression has been detected on osteoclasts andosteoblastic precursor cells, and administration of a CB₂ agonist inmice caused a dose-dependent increase in bone formation (Grotenhermen,F. and Muller-Vahl, K., Expert Opin. Pharmacother., 2003, 4(12),2367-2371). Cannabinoid inverse agonists, including the CB₂-selectiveinverse agonist SR144528, have been shown to inhibit osteoclast activityand reverse ovariectomy-induced bone loss in mice, which is a model forpost-menopausal osteoporosis (Ralston, S. H., et al., Nature Medicine,2005, 11, 774-779). Thus, CB₂ modulators may be useful for the treatmentand prevention of osteoporosis, osteoarthritis, and bone disorders.

Artherosclerosis is a chronic inflammatory disease and is a leadingcause of heart disease and stroke. CB₂ receptors have been detected inboth human and mouse atherosclerotic plaques. Administration of lowdoses of THC in apolipoprotein E knockout mice slowed the progression ofatherosclerotic lesions, and these effects were inhibited by theCB₂-selective antagonist SR144528 (Steffens, S., et al., Nature, 2005,434, 782-786). Thus, compounds with activity at the CB₂ receptor may beclinically useful for the treatment of atheroscelorsis.

CB₂ receptors are expressed on malignant cells of the immune system andtargeting CB₂ receptors to induce apoptosis may constitute a novelapproach to treating malignancies of the immune system. Selective CB₂agonists induce regression of malignant gliomas (Sanchez, C., et al.,Cancer Res., 2001, 61, 5784-5789), skin carcinomas (Casanova, M. L., etal., J. Clin. Invest., 2003, 111, 43-50), and lymphomas (McKallip, R.J., et al., Blood, 2002, 15(2), 637-634). Thus, CB₂ modulators may haveutility as anticancer agents against tumors of immune origin.

Activation of CB₂ receptors has been demonstrated to protect the heartagainst the deleterious effects of ischemia and reperfusion (Lepicier,P., et al., Brit. J. Pharm. 2003, 139, 805-815; Bouchard, J.-F., et al.,Life Sci. 2003, 72, 1859-1870; Filippo, C. D., et al., J. Leukoc. Biol.2004, 75, 453-459). Thus, CB₂ modulators may have utility for thetreatment or prophylaxis of cardiovascular disease and the developmentof myocardial infarction.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the duration oftreatment, the severity of the condition being treated and the conditionand prior medical history of the patient being treated. However, it iswithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved. Inthe treatment of certain medical conditions, repeated or chronicadministration of compounds of the invention may be required to achievethe desired therapeutic response. “Repeated or chronic administration”refers to the administration of compounds of the invention daily (i.e.,every day) or intermittently (i.e., not every day) over a period ofdays, weeks, months, or longer. In particular, the treatment of chronicpainful conditions is anticipated to require such repeated or chronicadministration of compounds of the invention. Compounds of the inventionmay become more effective upon repeated or chronic administration suchthat the therapeutically effective doses on repeated or chronicadministration may be lower than the therapeutically effective dose froma single administration.

Compounds of the invention can also be administered as a pharmaceuticalcomposition comprising the compounds of interest in combination with oneor more pharmaceutically acceptable carriers. The phrase“therapeutically effective amount” of the compound of the inventionmeans a sufficient amount of the compound to treat disorders, at areasonable benefit/risk ratio applicable to any medical treatment. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the invention will be decided by the attendingphysician within the scope of sound medical judgment. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed; and like factorswell-known in the medical arts. For example, it is well within the skillof the art to start doses of the compound at levels lower than requiredto achieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

Compounds of the invention may be administered alone, or in combinationwith one or more other compounds of the invention, or in combination(i.e. co-administered) with one or more additional pharmaceuticalagents. For example, a compound the invention, or a pharmaceuticallyacceptable salt or solvate thereof, may be administered in combinationwith acetaminophen, or with one or more nonsteroidal anti-inflammatorydrug (NSAID) such as, but not limited to, aspirin, diclofenac,diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen,ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid,mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide,nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam,sulfasalazine, sulindac, tolmetin and zomepirac. In certain embodimentsof the invention, the nonsteroidal anti-inflammatory drug (NSAID) isibuprofen. Combination therapy includes administration of a singlepharmaceutical dosage formulation containing one or more of thecompounds of invention and one or more additional pharmaceutical agents,as well as administration of the compounds of the invention and eachadditional pharmaceutical agent, in its own separate pharmaceuticaldosage formulation. For example, a compound of the invention and one ormore additional pharmaceutical agents, may be administered to thepatient together, in a single oral dosage composition having a fixedratio of each active ingredient, such as a tablet or capsule; or eachagent may be administered in separate oral dosage formulations.

Where separate dosage formulations are used, compounds of the inventionand one or more additional pharmaceutical agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

The total daily dose of the compounds of this invention administered toa human or other animal range from about 0.01 mg/kg body weight to about100 mg/kg body weight. More preferable doses can be in the range of fromabout 0.03 mg/kg body weight to about 30 mg/kg body weight. If desired,the effective daily dose can be divided into multiple doses for purposesof administration. Consequently, single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose. It isunderstood that the effective daily dose may vary with the duration ofthe treatment.

e. PHARMACEUTICAL COMPOSITIONS

The present invention further provides pharmaceutical compositions thatcomprise compounds of the present invention or a pharmaceuticallyacceptable salt or solvate thereof. The pharmaceutical compositionscomprise compounds of the present invention that may be formulatedtogether with one or more non-toxic pharmaceutically acceptablecarriers.

Another aspect of the present invention is a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt thereof, and one or more pharmaceutically acceptable carriers,alone or in combination with one or more nonsteroidal anti-inflammatorydrug (NSAID).

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq). The saltscan be prepared in situ during the final isolation and purification ofthe compounds of the invention or separately by reacting a free basefunction with a suitable organic acid. Representative acid additionsalts include, but are not limited to acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use.

The present invention contemplates compounds of formula (I) formed bysynthetic means or formed by in vivo biotransformation of a prodrug.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

f. GENERAL SYNTHESIS

This invention is intended to encompass compounds of the invention whenprepared by synthetic processes or by metabolic processes. Preparationof the compounds by metabolic processes includes those occurring in thehuman or animal body (in vivo) or processes occurring in vitro.

The compounds of the invention may be prepared by a variety of processeswell known for the preparation of compounds of this class. For example,the compounds of the invention wherein the groups R_(g), R₁, R₂, R₃, R₄,R₉, R₁₀, R₃₁, R₃₂, R₄₁, R₄₂, Z₁, Z₂, G₁, and L₁ have the meanings as setforth in the summary section unless otherwise noted, can be synthesizedas shown in Schemes 1-15.

As used in the descriptions of the schemes and the examples, certainabbreviations are intended to have the following meanings: aq. foraqueous; DME for dimethoxyethane, DMF for N,N-dimethylformamide; dppffor, 1′-bis(diphenylphosphino)ferrocene, EtOAc for ethyl acetate, EtOHfor ethanol, Et₃N for triethylamine, HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, Et₂O for diethyl ether, Et₃N for triethylamine,HPLC for high performance liquid chromatography, Ph for phenyl; mesylfor methanesulfonate; MeOH for methanol, min for minute or minutes; n-Bufor n-butyl; DMSO for dimethylsulfoxide; dppf for1,1′-bis(diphenylphosphino)ferrocene; TFA for trifluoroacetic acid; THFfor tetrahydrofuran; Ts or tosyl for p-CH₃PhS(O)₂O—; and Tf or triflatefor CF₃S(O)₂O—.

As shown in Scheme 1, compounds of formula (1) containing an amine groupwhen treated with compounds of formula (2), wherein X is chloro or —OHunder coupling conditions known to one skilled in the art, will providecompounds of formula (3). Typical conditions for the reaction ofcompounds of formula (2) wherein X is chloro and compounds of formula(1) include but are not limited to stirring an equimolar mixture of thecompounds in solvents such as chloroform, dichloromethane or THF in thepresence of a base such as but not limited to diisopropylethylamine at0-30° C. for 8-24 hours. Acid coupling conditions of compounds offormula (2), wherein X is —OH and compounds of formula (1), includestirring an equimolar mixture of the compounds with a coupling reagentsuch as but not limited to bis(2-oxo-3-oxazolidinyl)phosphinic chloride(BOPCl), 1,3-dicyclohexylcarbodiimide (DCC), polymer supported1,3-dicyclohexylcarbodiimide (PS-DCC),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) along with a coupling auxiliary such as but not limited to1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate(HOBT) in the presence or absence of a base such as but not limited toN-methyl morpholine, diisopropylethylamine in a solvent such as, but notlimited to, THF, N,N-dimethylacetamide, N,N-dimethylformamide, pyridine,chloroform, or mixtures thereof. Typical reactions can be carried outbetween 0-65° C. or may be carried out in a microwave reactor tofacilitate the coupling.

As shown in Scheme 2, compounds of formula (3) may be converted intocompounds of formula (4) which are representative compounds of thepresent invention. Typical conditions include, but are not limited to,the treatment of compounds of formula (3) with sodium hydride in DMF at0° C., followed by the addition of reagents such as R₁—Y, wherein R₁ isas defined in formula (I) and Y is chloro, bromo, iodo, tosyl, mesyl ortriflate. Alternatively, other bases such as potassium hydroxide orpotassium tert-butoxide in a mixture of THF and DMF, followed bytreatment with R₁—Y will also provide compounds of formula (4).

Alternatively, compounds of formula (4) may also be prepared accordingto the methods outlined in Scheme 3. Compounds of formula (1) whentreated with sodium hydride in DMF at 0° C., followed by the addition ofreagents such as R₁—Y, wherein Y is chloro, bromo, iodo, tosyl, mesyl ortriflate provide compounds of formula (6). Alternatively, compounds offormula (1) may be heated neat or in the presence of a minimal amount ofsolvent to facilitate mixing with compounds of formula R₁—Y to obtaincompounds of formula (6). Compounds of formula (6) may be isolated as asalt or a free base. The treatment of compounds of formula (6) withcompounds of formula (2), wherein X is chloro or —OH, under couplingconditions as outlined in Scheme 1 can generate compounds of formula(4).

As outlined in Scheme 4, compounds of formula (7), wherein R₁₀₀ ishalide or triflate and which can be prepared according to the methodsoutlined in Schemes 1-3, when treated with a boronic acid of formulaR₃B(OH)₂, wherein R₃ is aryl, arylalkenyl, cycloalkyl, heterocycle orheteroaryl, a palladium catalyst such asdichlorobis(triphenyl)phosphine)palladium (II) and sodium carbonate in amixture of solvents which include but are not limited to variousmixtures of DME, ethanol and water under heated conditions providecompounds of formula (4) wherein R₃ is alkenyl, aryl, arylalkenyl,cycloalkyl, heterocycle or heteroaryl.

As outlined in Scheme 5, compounds of formula (9) wherein R₁₀₀ is halideor triflate and which can be prepared according to the methods outlinedin Schemes 1-3, when treated with a boronic acid of formula R₂B(OH)₂,wherein R₂ is aryl, arylalkenyl, cycloalkyl, heterocycle or heteroaryland a palladium catalyst according to the methods outlined is Scheme 4can provide compounds of formula (4) wherein R₂ is aryl, arylalkenyl,cycloalkyl, heterocycle or heteroaryl.

Scheme 6 describes another alternative method for the preparation ofcompounds of formula (4). Compounds of formula (11) when treated withoxalyl chloride in dichloromethane containing a catalytic amount of DMFwill provide the acid chloride of formula (12). The acid chloride offormula (12) when treated with potassium thiocyanate in acetone canprovide compounds of formula (13). Compounds of formula (13) whentreated with an amine of formula R₁—NH₂ in solvents such as but notlimited to THF can provide compounds of formula (14). Compounds offormula (14) when treated with substituted alpha-bromo-ketones offormula (15) in ethanol or mixtures of ethanol and toluene under heatedconditions will provide compounds of formula (4).

Compounds of formula (I) wherein L₁ is —NH—, may be prepared as outlinedin Scheme 7. Compounds of formula (16) when treated with an amine offormula (17), wherein R₄ is defined in formula (I), will providecompounds of formula (18). Compounds of formula (18) when treated withcompounds of formula (6) can provide compounds of formula (19).

Alternatively, compounds of formula (6) when treated with an isocyanateof formula (20) provide compounds of formula (19).

Similarly, compounds of formula (6) when treated with carbonyldiimidazole, followed by treatment with methyl iodide, can provide theimidazolide compounds of formula (21). Compounds of formula (21) whentreated with an amine of formula (22) can provide compounds of formula(19A).

As shown in Scheme 10, compounds of formula (23) when treated at lowtemperatures with an organolithium reagent such as but not limited toR₃₂Li or a Grignard reagent such as but not limited to R₃₂MgBr can beconverted to compounds of formula (24). The reaction is typicallyconducted in a solvent such as but not limited to diethyl ether.

As shown in Scheme 11, compounds of formula (25) when treated withpyrrolidine and p-toluenesulfonic acid monohydrate in a solvent such asbut not limited to cyclohexane at reflux followed by treatment withsulfur and cyanamide in a solvent such as but not limited to methanol attemperatures between 0-70° C., can provide compounds of formula (1).

As shown in Scheme 12, compounds of formula (25) when treated withamines of formula R₁NH₂, in the presence of molecular sieves in asolvent such as, but not limited to, acetonitrile, at a temperaturesranging from about 25° C. to about 80° C., followed by treatment withpotassium thiocyanate and iodine at temperatures between 40-80° C.,provide compounds of formula (6).

Certain compounds of formula (I) where R₄ or R₉ is phenyl and saidphenyl is substituted with the group —OR₁₀₂ can be prepared using themethods described in Scheme 13.

Compounds of formula (27), wherein R₁₀₁ represents the optionalsubstituents of R₄ and R₉ of formula (I), z is 0, 1, 2, 3, or 4, andR₁₀₂ is R₁₀, alkyl, alkoxyalkyl, haloalkyl, NZ₁Z₂—(CR₄₁R₄₂)_(p)—, orG₁-(CR₄₁R₄₂)_(p)— can be prepared from compounds of formula (26) byreaction with an alcohol HOR₁₀₂ in the presence of a base such as, butnot limited to, potassium tert-butoxide or sodium tert-butoxide in asolvent such as, but not limited to, tetrahydrofuran ordimethylformamide at temperatures between about 0° C. and 50° C. Incertain instances, a protecting group may be attached to a functionalgroup present in R₁₀₂. Such protecting groups can be removed usingmethods well-known to those skilled in the art. The group R₁₀₂ can alsobe further transformed to provide other compounds of the invention usingstandard chemical techniques well-known to those skilled in the art suchas alkylation, acylation, and reductive amination.

Certain compounds of formula (I) wherein R₄ or R₉ is phenyl and saidphenyl is substituted with a group R₁₀₃, can be prepared according tothe carbon-carbon bond forming reactions described in Scheme 14.

Compounds of formula (29), wherein R₁₀₁ represents the optionalsubstituents of R₄ and R₉ of formula (I), z is 0, 1, 2, 3, or 4, andR₁₀₃ is selected from the group consisting of alkenyl,alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl,alkylcarbonylalkyl, alkylsulfinylalkyl,alkyl-S(O)₂—(CR₄₁R₄₂)_(p)═C(R₄₁)—, alkyl-S(O)₂—(CR₄₁R₄₂)_(p)—,alkyl-S—(CR₄₁R₄₂)_(p)—, alkynyl, carboxyalkyl, cyano, cyanoalkyl,formylalkyl, haloalkyl, hydroxyalkyl, —C(R₄₁)═N—O(R₄₂), and—(CR₄₁R₄₂)_(p)—C(R₄₁)═N—O(R₄₂), can be prepared from compounds offormula (28). Reactions well-known in the chemical literature foreffecting these transformations include the Suzuki, Heck, Stille,Sonogashira, and Negishi reactions. Typical reaction conditions for canbe found in the following references: Negishi, E. A. Handbook ofOrganopalladium Chemistry for Organic Synthesis; Wiley-Interscience: NewYork, 2002; Miyaura, N. Cross-Coupling Reactions: A Practical Guide;Springer: New York, 2002. More specifically, where R₁₀₃ isalkyl-S(O)₂—(CR₄₁R₄₂)_(p)═C(R₄₁)—, or alkenyl, compounds can be preparedusing palladium acetate, tri(o-tolyl)phosphine as the ligand,triethylamine as base with the corresponding vinyl sulfone, or alkeneunder microwave conditions at temperatures from 140-180° C. In theconversion of (28) to (29), the —Br of (28) may also be a triflate, —I,—Cl, a boronic acid (or derivative), stannyl or the like.

Certain compounds of formula (I) wherein R₄ or R₉ is phenyl, can beprepared according to the method shown in Scheme 15.

Compounds of the invention of formula (31), wherein R₁₀₁ represents theoptional substituents of R₄ and R₉ of formula (I), z is 0, 1, 2, 3, or4, and NR₁₀₄R₁₀₅ is NZ₁Z₂ or G₁, can be prepared from compounds offormula (30) by a reductive amination reaction. The reductive aminationreaction is well known to those skilled in the art. For example,reaction of compounds (30) with amines HNR₁₀₄R₁₀₅ in solvents such as,but not limited to, acetonitrile, tetrahydrofuran, dichloromethane ordichloroethane, in the presence of a reducing agent such as, but notlimited to, sodium cyanoborohydride or sodium triacetoxyborohydride, canprovide compounds (31). The reaction may be conducted in the presence ofan acid (e.g., acetic acid).

It will be appreciated that the synthetic schemes and specific examplesas illustrated in the Examples section are illustrative and are not tobe read as limiting the scope of the invention as it is defined in theappended claims. All alternatives, modifications, and equivalents of thesynthetic methods and specific examples are included within the scope ofthe claims.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Examples section. Reactions may be worked up in the conventionalmanner, e.g. by eliminating the solvent from the residue and furtherpurified according to methodologies generally known in the art such as,but not limited to, crystallization, distillation, extraction,trituration and chromatography. Unless otherwise described, the startingmaterials and reagents are either commercially available or may beprepared by one skilled in the art from commercially available materialsusing methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protecting Groups in ChemicalSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention may be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation. Following Examples may be used for illustrative purposes andshould not be deemed to narrow the scope of the invention.

EXAMPLES Example 1N-[(2Z)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 1A 2,2,3,3-tetramethylcyclopropanecarbonyl chloride

To a solution of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.50 g,3.5 mmol) in 18 mL of methylene chloride at 0° C. was added oxalylchloride (0.61 mL, 7.0 mmol) and a catalytic amount of dimethylformamide(2 drops). The solution was stirred at ambient temperature for 1 hour,and then concentrated under reduced pressure to provide 0.56 g of thetitle compound.

Example 1B 2,2,3,3-tetramethyl-N-1,3-thiazol-2-ylcyclopropanecarboxamide

To a solution of 2-aminothiazole (0.39 g, 3.9 mmol) in 10 mL ofmethylene chloride at 0° C. was added a solution of the product fromExample 1A in 8 mL of chloroform, followed by triethylamine (1.0 mL, 7.7mmol). The mixture was stirred for 7 hours at 35° C., cooled to ambienttemperature and diluted with water. The phases were separated and theaqueous phase was extracted with methylene chloride. The combinedorganic extracts were washed twice with water and then brine, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.Purification by column chromatography (SiO₂, 30-60% ethylacetate/hexanes gradient) afforded 0.11 g (14%) of the title compound.¹H NMR (CDCl₃, 300 MHz) δ ppm 1.18 (s, 1H), 1.25 (s, 6H), 1.35 (s, 6H),6.92 (d, J=3.4 Hz, 1H), 7.39 (d, J=3.4 Hz, 1H), 10.7 (s, 1H); MS(DCI/NH₃) m/z 225 (M+H)⁺. Anal. Calculated for C₁₁H₁₆N₂OS: C, 58.90; H,7.19; N, 12.49. Found: C, 59.03; H, 7.34; N, 12.34.

Example 1CN-[(2Z)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide

To a solution of Example 1B (0.16 g, 0.71 mmol) in 3.5 mL of 4:1tetrahydrofuran:dimethylformamide at 0° C. was added potassium hydroxide(90 mg, 1.7 mmol). After stirring for 1 hour at room temperature,2-bromoethyl methyl ether (73 μL, 7.1 mmol) was added and the solutionwas heated to 65° C. for 14 hours. The solution was allowed to cool toambient temperature and then diluted with ethyl acetate and washed twicewith water and then brine. The organic extract was dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Purificationby column chromatography (SiO₂, 30-50% ethyl acetate/hexanes gradient)afforded 22 mg (11%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δ1.25 (s, 12H), 1.75 (s, 1H), 3.32 (s, 3H), 3.74 (t, J=5.6 Hz, 2H), 4.44(t, J=5.4 Hz, 2H), 6.95 (d, J=3.4 Hz, 1H), 7.48 (t, J=3.7 Hz, 1H); MS(DCI/NH₃) m/z 283 (M+H)⁺. Anal. Calculated for C₁₄H₂₂N₂O₂S: C, 59.54; H,7.85; N, 9.92. Found: C, 59.76; H, 7.97; N, 9.91.

Example 25-chloro-2-methoxy-N-[(2Z)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 2A 3-(2-methoxyethyl)-1,3-thiazol-2(3H)-imine hydrobromide

A mixture of 2-aminothiazole (15 g, 0.15 mol) and 2-bromoethyl methylether (17 mL, 0.18 mol) were heated at 85° C. for 16 hours. Aftercooling to ambient temperature the resulting solid was triturated twicewith isopropyl alcohol to afford 26 g (72%) of the title compound. ¹HNMR (DMSO-d₆, 300 MHz) δ ppm 3.27 (s, 3H), 3.63 (t, J=5.1 Hz, 2H), 4.23(t, J=4.9 Hz, 2H), 7.02 (d, J=4.7 Hz, 1H), 7.38 (d, J=4.4 Hz, 1H), 9.52(s, 1H); MS (DCI/NH₃) m/z 159 (M+H)⁺.

Example 2B5-Chloro-2-methoxy-N-[(2Z)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of the product from Example 2A (0.77 g, 3.2 mmol) and5-chloro-2-methoxybenzoic acid (0.50 g, 2.7 mmol) in 14 mL of THF at 0°C. was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 1.24 g, 3.2 mmol) andN,N-diisopropylethylamine (1.1 mL, 6.2 mmol). The mixture was heated to65° C. for 2.5 hours, cooled to ambient temperature and then dilutedwith ethyl acetate. The mixture was washed twice with water, thensaturated aqueous sodium bicarbonate, and brine. The organic extract wasdried over magnesium sulfate, and concentrated under reduced pressure.Purification by column chromatography (SiO₂, 20-35% ethylacetate/hexanes gradient) afforded 0.38 g (43%) of the title compound.¹H NMR (CDCl₃, 300 MHz) δ ppm 3.35 (s, 3H), 3.72-3.81 (m, 2H), 3.91 (s,3H), 4.41-4.48 (m, 2H), 6.65 (d, J=4.7 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H),7.16 (d, J=4.7 Hz, 1H), 7.34 (dd, J=8.8, 3.1 Hz, 1H), 7.99 (d, J=2.7 Hz,1H); MS (DCI/NH₃) m/z 349 (M+H)⁺. Anal. Calculated for C₁₈H₂₄N₂O₃S: C,62.04; H, 6.94; N, 8.04. Found: C, 62.24; H, 7.08; N, 8.04.

Example 3N-[(2Z)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]cycloheptanecarboxamide

Cycloheptanecarboxylic acid (29 mg, 0.20 mmol), 3 equiv of polymer bounddicyclohexylcarbodiimide (PS-DCC), 1-hydroxybenzotriazole hydrate (HOBT,22 mg, 0.16 mmol), N,N-diisopropylethylamine (62 mg, 0.50 mmol), and theproduct of Example 2A (39 mg, 0.16 mmol) were combined indimethylacetamide (DMA, 2.8 mL) and heated in a microwave to 100° C. for420 seconds. The mixture was filtered through Si-Carbonate (6 mL-1 gcartridge from Silicycle Chemical Division) and then concentrated todryness. The residue was dissolved in 1:1 DMSO/MeOH and purified byreverse phase HPLC to afford the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.39-1.72 (m, 11H) 1.83-1.95 (m, 2H) 2.46-2.52 (m, 1H)3.23-3.26 (m, 3H) 3.67 (t, 2H) 4.29 (t, 2H) 6.76-6.97 (d, 1H) 7.30-7.43(d, 1H); MS (ESI) m/z 283 (M+H)⁺.

Example 4N-[(2Z)-3-(3-methoxypropyl)-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 4A 3-(3-methoxypropyl)-1,3-thiazol-2(3H)-imine hydrobromide

A mixture of 2-aminothiazole (1.0 g, 10 mmol) and1-bromo-3-methoxypropane (1.8 g, 12 mmol) were heated at 85° C. for 16hours. The solid was cooled to ambient temperature, triturated withethanol, and then collected by filtration to provide 1.2 g (48%) of thetitle compound. MS (DCI/NH₃) m/z 173 (M+H)⁺.

Example 4BN-[(2Z)-3-(3-methoxypropyl)-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide

The product of Example 4A (0.60 g, 2.4 mmol) and2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.34 g, 2.4 mmol) wereprocessed using the method described in Example 2B. Purification bycolumn chromatography (SiO₂, 20-40% ethyl acetate/hexanes gradient)afforded 0.33 g (47%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 1.21 (s, 6H), 1.34 (s, 6H), 1.56 (d, J=5.4 Hz, 1H), 2.00-2.13 (m,2H), 3.31-3.39 (m, 5H), 4.23 (t, J=6.8 Hz, 2H), 6.50 (d, J=4.7 Hz, 1H),6.88 (d, J=4.7 Hz, 1H); MS (DCI/NH₃) m/z 297 (M+H)⁺. Anal. Calculatedfor C₁₅H₂₄N₂O₂S: C, 60.78; H, 8.27; N 9.45. Found: C, 60.78; H, 8.27; N,9.34.

Example 5N-[(2Z)-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 5A 3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-iminehydrobromide

A mixture of 4-methylthiazol-2-ylamine (0.75 g, 6.5 mmol) and2-bromoethyl methyl ether (730 μL, 7.8 mmol) was heated at 85° C. for 15hours. The mixture was cooled to ambient temperature and the resultingsolid was triturated with isopropanol. Recrystallization from hotethanol afforded 0.56 g (34%) of the title compound. ¹H NMR (DMSO-d₆,300 MHz) δ ppm 2.25 (d, J=1.4 Hz, 3H) 3.25 (s, 3H) 3.57 (t, J=5.1 Hz,2H) 4.15 (t, J=5.1 Hz, 2H) 6.68 (d, J=1.4 Hz, 1H) 9.40 (s, 1H); MS(DCI/NH₃) m/z 173 (M+H)⁺.

Example 5BN-[(2Z)-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide

The product of Example 5A (0.30 g, 1.2 mmol) and2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.19 g, 1.3 mmol) wereprocessed using the method described in Example 2B. Purification bycolumn chromatography (SiO₂, 20-40% ethyl acetate/hexanes gradient)afforded 0.14 g (41%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 1.21 (s, 6H), 1.34 (s, 6H), 1.59 (s, 1H), 2.30 (s, 3H), 3.30 (s,3H), 3.70 (t, J=5.09 Hz, 2H), 4.25 (t, J=5.26 Hz, 2H), 6.09 (s, 1H); MS(DCI/NH₃) m/z 297 (M+H)⁺. Anal. Calculated for C₁₅H₂₄N₂O₂S: C, 60.78; H,8.16; N, 9.45. Found: C, 60.79; H, 7.82; N, 9.36.

Example 6ethyl((2Z)-3-(2-methoxyethyl)-2-{[(2,2,3,3-tetramethylcyclopropyl)carbonyl]imino}-2,3-dihydro-1,3-thiazol-4-yl)acetateExample 6Aethyl[2-imino-3-(2-methoxyethyl)-2,3-dihydro-1,3-thiazol-4-yl]acetatehydrobromide

A mixture of (2-aminothiazol-4-yl)acetic acid ethyl ester (18.6 g, 100mmol) and 2-bromoethyl methyl ether (15.3 g, 110 mmol) were processedusing the method described in Example 2A to afford 14.1 g (83%) of thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.14-1.28 (m, 3H) 3.24(s, 3H) 3.54 (t, J=5 Hz, 2H) 3.91 (s, 2H) 4.04-4.25 (m, 4H) 6.92 (s, 1H)9.50 (s, 1H); MS (DCI/NH₃) m/z 231 (M+H)⁺.

Example 6Bethyl((2Z)-3-(2-methoxethyl)-2-{[(2,2,3,3-tetramethylcyclopropyl)carbonyl]imino}-2,3-dihydro-1,3-thiazol-4-yl)acetate

The product of Example 6A (2.3 g, 10 mmol) and2,2,3,3-tetramethylcyclopropane carboxylic acid (1.6 g, 11 mmol) wereprocessed as described using the method described in Example 2B toafford 2.1 g (54%) of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.06-1.33 (m, 15H) 1.48 (s, 1H) 3.22 (s, 3H) 3.59 (t, J=5 Hz, 2H)3.91 (s, 2H) 4.12 (t, J=7 Hz, 2H) 4.14-4.24 (m, 2H) 6.69 (s, 1H); MS(DCI/NH₃) m/z 369 (M+H)⁺. Anal. Calculated for C₁₈H₂₈N₂O₄S C, 68.67; H,7.66; N, 7.62. Found: C, 68.67; H, 7.66; N, 7.60.

Example 7ethyl(2Z)-3-(2-methoxyethyl)-2-{[(2,2,3,3-tetramethylcyclopropyl)carbonyl]imino}-2,3-dihydro-1,3-thiazole-4-carboxylateExample 7A ethyl2-imino-3-(2-methoxyethyl)-2,3-dihydro-1,3-thiazole-4-carboxylatehydrobromide

A mixture of 2-aminothiazole-4-carboxylic acid ethyl ester (17.2 g, 100mmol) and 2-bromoethyl methyl ether (15.3 g, 110 mmol) were processedusing the method described in Example 2A to afford 17.1 g (83%) of thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.30 (t, J=7 Hz, 3H)3.22 (s, 3H) 3.60 (t, J=5 Hz, 2H) 4.32 (t, J=7 Hz, 2H) 4.35-4.61 (m,2H), 7.84 (s, 1H), 9.76 (s, 1H); MS (DCI/NH₃) m/z 231 (M+H)⁺.

Example 7Bethyl(2Z)-3-(2-methoxyethyl)-2-{[(2,2,3,3-tetramethylcyclopropyl)carbonyl]imino}-2,3-dihydro-1,3-thiazole-4-carboxylate

The product of Example 7A (2.3 g, 10 mmol) and2,2,3,3-tetramethylcyclopropane carboxylic acid (1.6 g, 11 mmol) wereprocessed using the method described in Example 2B to afford 1.9 g (53%)of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.11-1.36 (m,12H) 1.53 (s, 1H) 3.21 (s, 3H) 3.31 (s, 3H) 3.53-3.62 (m, 2H) 4.30 (q,J=7 Hz, 2H) 4.62-4.75 (m, 2H) 7.77 (s, 1H); MS (DCI/NH₃) m/z 355 (M+H);Anal. Calculated for C₁₇H₂₆N₂O₄S: C, 57.61; H, 7.39; N, 7.86. Found: C,57.86; H, 7.67; N, 7.85.

Example 8N-[(2Z)-4-(hydroxymethyl)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide

To a solution of the product of Example 7B (0.355 g, 1.00 mmol) in 100mL of THF at 0° C. was added lithium borohydride (10 mL of a 2.0 Msolution in THF) and the resulting solution was allowed to warm toambient temperature and stirred overnight. The mixture was quenched withwater and then diluted with saturated aqueous Na₂CO₃ and extracted twicewith ethyl acetate. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered, and concentrated. Purification by columnchromatography (SiO₂, 0-50% ethyl acetate/hexanes gradient) afforded0.278 g (89%) of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.20 (d, 12H) 1.47 (s, 1H) 3.24 (s, 3H) 3.64 (t, J=6 Hz, 2H) 4.30 (t,J=6 Hz, 2H) 4.50 (d, J=5 Hz, 2H) 5.75 (s, 1H) 6.68 (s, 1H); MS (DCI/NH3)m/z 313 (M+H)⁺; Anal. Calculated for C₁₅H₂₄N₂O₃S.0.2H₂O: C, 57.01; H,7.78; N, 8.86. Found: C, 56.90; H, 7.61; N, 8.86.

Example 92-ethoxy-N-[(2Z)-3-(2-methoxyethyl)-4-(trifluoromethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 9A 2-ethoxy-N-(4-trifluoromethyl-thiazol-2-yl)-benzamide

A solution of 2-ethoxybenzoic acid (0.75 g, 4.5 mmol) in 23 mL ofmethylene chloride at 0° C. was treated with oxalyl chloride (0.44 mL,4.9 mmol) followed by 2 drops of dimethylformamide. The solution wasstirred at ambient temperature for 1 hour and then concentrated underreduced pressure to provide 0.83 g of 2-ethoxybenzoyl chloride. To asolution of 4-trifluoromethylthiazol-2-ylamine (0.50 g, 3.0 mmol) in 10mL THF at 0° C. was added a solution of the freshly prepared acidchloride in 5 mL of THF and 2 mL of methylene chloride, followed bytriethylamine (1.0 mL, 6.6 mmol). The reaction mixture was warmed to 65°C. and stirred 8 hours. The mixture was diluted with ethyl acetate andwashed twice with water, then brine. The organic extract was dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.Purification by column chromatography (SiO₂, 30-50% ethylacetate/hexanes gradient) afforded 0.47 g (50%) of the title compound.¹H NMR (CDCl₃, 300 MHz) δ ppm 1.66 (t, J=6.95 Hz, 3H), 4.38 (q, J=6.89Hz, 2H), 7.03-7.10 (m, 2H), 7.17 (d, J=7.80 Hz, 1H), 7.42 (s, 1H), 8.29(dd, J=7.97, 1.86 Hz, 1H). MS (DCI/NH₃) m/z 317 (M+H)⁺.

Example 9B2-ethoxy-N-[(2Z)-3-(2-methoxyethyl)-4-(trifluoromethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 9A (0.47 g, 1.5 mmol) and1-bromo-2-methoxy-ethane (0.16 ml, 1.6 mmol) were processed using themethod described in Example 1B. Purification by column chromatography(SiO₂, 30-40% ethyl acetate/hexanes gradient) afforded 0.06 g (11%) ofthe title compound. ¹H NMR (DMSO-d₆, 300 MHz) δ ppm 1.24 (t, J=6.95 Hz,3H), 3.02 (s, 3H), 3.36-3.63 (m, 2H), 3.86-4.02 (m, 1H), 4.13 (q, J=7.12Hz, 2H), 4.21-4.33 (m, 1H), 7.08 (t, J=7.46 Hz, 1H), 7.17 (d, J=8.14 Hz,1H), 7.40 (dd, J=7.46, 1.70 Hz, 1H), 7.46-7.56 (m, 1H), 8.09 (s, 1H); MS(DCI/NH₃) m/z 375 (M+H)⁺. Anal. Calculated for C₁₆H₁₇F₃N₂O₃S.0.2 H₂O: C,50.84; H, 4.64; N, 7.41. Found: C, 50.62; H, 4.35; N, 7.61.

Example 10N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 10A 3-(2-Methoxyethyl)-5-methyl-3H-thiazol-2-ylideneaminehydrobromide

A mixture of 5-methyl-thiazol-2-ylamine (1.0 g, 8.8 mmol) and2-bromoethyl methyl ether (1.0 mL, 11 mmol) were heated at 85° C. for 16hours. The mixture was cooled to ambient temperature, triturated withethanol and the solid was collected by filtration to afford 0.90 g (40%)of the title compound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 2.25 (d, J=1.4 Hz,3H), 3.36 (s, 3H), 3.72-3.81 (m, 2H), 4.36-4.43 (m, 2H), 6.61 (d, J=1.7Hz, 1H), 9.54 (s, 1H); MS (DCI/NH₃) m/z 173 (M+H)⁺.

Example 10BN-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide

The product of Example 10A (0.40 g, 1.6 mmol) and2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.25 g, 1.8 mmol) wereprocessed using the method described in Example 2B. Purification bycolumn chromatography (SiO₂, 20-40% ethyl acetate/hexanes gradient)afforded 0.30 g (63%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 1.21 (s, 6H), 1.33 (s, 6H), 1.52 (s, 1H), 2.22 (s, 3H), 3.35 (s,3H), 3.68 (t, J=5.09 Hz, 2H), 4.24 (t, J=4.92 Hz, 2H), 6.67 (s, 1H); MS(DCI/NH₃) m/z 297 (M+H)⁺. Anal. Calculated for C₁₅H₂₄N₂O₂S: C, 60.78; H,8.16; N, 9.45. Found: C, 60.69; H, 8.31; N, 9.19.

Example 112-ethoxy-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide

To the product of Example 10A (0.55 g, 2.2 mmol) and 2-ethoxybenzoylchloride (0.33 g, 1.8 mmol) in 10 mL of THF at 0° C. was addedtriethylamine (0.55 mL, 4.0 mmol). The solution was stirred at 65° C.for 4 hours then allowed to cool to ambient temperature and diluted withethyl acetate. The solution was washed twice with water and then brine.The combined aqueous washings were extracted with ethyl acetate. Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated under reduced pressure. Purification by columnchromatography (SiO₂, 20-30% ethyl acetate/hexanes gradient) afforded0.28 g (42%) of the title compound. ¹H NMR (DMSO-d₆, 300 MHz) δ ppm 1.31(t, J=7.0 Hz, 3H), 2.26 (d, J=1.4 Hz, 3H), 3.25 (s, 3H), 3.69 (t, J=5.3Hz, 2H), 4.05 (q, J=7.1 Hz, 2H), 4.30 (t, J=5.3 Hz, 2H), 6.95 (t, J=7.5Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.20 (d, J=1.4 Hz, 1H), 7.32-7.41 (m,1H), 7.68 (dd, J=7.6, 1.9 Hz, 1H); MS (DCI/NH₃) m/z 321 (M+H)⁺. Anal.Calculated for C₁₆H₂₀N₂O₃S.0.2H₂O: C, 59.31; H, 6.35; N, 8.65. Found: C,59.18; H, 6.02; N, 8.29.

Example 123-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-methylbenzamideExample 12A 3-(2-Methoxyethyl)-4,5-dimethyl-3H-thiazol-2-ylideneaminehydrobromide

A mixture of 4,5-dimethylthiazol-2-ylamine (9.0 g, 70 mmol) and2-bromoethyl methyl ether (7.9 mL, 84 mmol) were heated at 85° C. for 12hours. The mixture was cooled to ambient temperature and then trituratedwith isopropanol. The solid was collected by filtration and dried undervacuum to provide 10 g (56%) of the title compound. ¹H NMR (DMSO-d₆, 300MHz) δ ppm 2.17 (s, 3H), 2.19 (s, 3H), 3.25 (s, 3H) 3.56 (t, J=5.1 Hz,2H) 4.16 (t, J=5.1 Hz, 2H) 9.41 (s, 1H); MS (DCI/NH₃) m/z 129 (M+H)⁺.

Example 12B3-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-methylbenzamide

The product of Example 12A (39 mg, 0.15 mmol) and3-fluoro-2-methylbenzoic acid (31 mg, 0.22 mmol) were processed usingthe method described in Example 3 to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.21-2.24 (m, 3H), 2.26-2.28 (m, 3H), 2.44-2.47(m, 3H), 3.24 (s, 3H), 3.66-3.71 (m, 2H), 4.35 (t, 2H), 7.21-7.31 (m,2H), 7.76 (d, 1H); MS (ESI) m/z 324 (M+H)⁺.

Example 135-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-methylbenzamideExample 13A 5-Fluoro-2-methyl-benzoyl chloride

A solution of 5-fluoro-2-methylbenzoic acid (380 mg, 2.47 mmol) inthionyl chloride (5 mL) was heated to reflux for 3 hours. The solutionwas cooled to ambient temperature and the volatile components wereremoved under reduced pressure. The residue was dissolved in freshtoluene (10 mL) and concentrated under reduced pressure twice and thenplaced under high vacuum to afford the title compound (420 mg).

Example 13B5-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-methylbenzamide

To a suspension of the product of Example 12A (549 mg, 2.05 mmol) andtriethylamine (0.859 mL, 6.16 mmol) in THF (6 mL) were added a solutionof the product from Example 13A in THF (2 mL). The mixture was heated atreflux for 14 hours, then cooled to ambient temperature and diluted withwater and CH₂Cl₂. The phases were separated and the organic extract waswashed with water and brine, dried (Na₂SO₄) and concentrated. Theresidue was dissolved in warm EtOAc (10 mL) and allowed to stand at roomtemperature for 14 hours. The crystals were isolated by filtration(EtOAc wash) to afford the title compound (450 mg, 68%). MS (ESI) m/z324 (M+H)⁺.

Example 143-methoxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-4-methylbenzamide

The product of Example 12A (39 mg, 0.15 mmol) and3-methoxy-4-methylbenzoic acid (37 mg, 0.22 mmol) were processed usingthe method described in Example 3 to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.21 (d, 6H), 2.26 (s, 3H), 3.26 (s, 3H), 3.74(t, 2H), 3.85 (s, 3H), 4.40 (t, 2H), 7.22 (d, 1H), 7.68-7.72 (m, 2H); MS(ESI) m/z 335 (M+H)⁺.

Example 152-ethoxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 12A (0.35 g, 1.3 mmol) and 2-ethoxybenzoic acid(0.43 g, 2.6 mmol) were processed using the methods described in Example13. Purification by column chromatography (SiO₂, 30-50% ethylacetate/hexanes gradient) afforded 0.078 g (18%) of the title compound.¹H NMR (CDCl₃, 300 MHz) δ ppm 1.46 (t, J=7.0 Hz, 3H), 2.18-2.31 (m, 6H),3.30 (s, 3H), 3.78 (t, J=5.3 Hz, 2H), 4.17 (d, J=7.1 Hz, 2H), 4.37 (s,2H), 6.89-7.04 (m, 2H), 7.36 (t, J=7.6 Hz, 1H), 7.96 (dd, J=7.8, 1.7 Hz,1H); MS (DCI/NH₃) m/z 335 (M+H)⁺. Anal. Calculated forC₁₇H₂₂N₂O₃S.0.1H₂O: C, 60.73; H, 6.65; N, 8.33. Found: C, 60.37; H,6.42; N, 8.31.

Example 16N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-1-naphthamide

The product of Example 12A (39 mg, 0.15 mmol) and 1-naphthoic acid (39mg, 0.22 mmol) were processed using the method described in Example 3 toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H),2.28 (s, 3H), 3.26 (s, 3H), 3.72-3.77 (m, 2H), 4.37-4.43 (m, 2H),7.52-7.60 (m, 3H), 7.95-7.99 (m, 1H), 8.02-8.06 (m, 1H), 8.28-8.31 (m,1H), 9.03-9.07 (m, 1H); MS (ESI) m/z 341 (M+H)⁺.

Example 17N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-naphthamide

The product of Example 12A (39 mg, 0.15 mmol) and 2-napthoic acid (39mg, 0.22 mmol) were processed using the method described in Example 3 toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.24 (s, 3H)2.29 (s, 3H) 3.28 (s, 3H) 3.80 (t, 2H) 4.49 (t, 2H) 7.55-7.62 (m, 2H)7.95-7.99 (m, 2H) 8.08 (d, 1H) 8.26-8.29 (m, 1H) 8.76 (s, 1H); MS (ESI)m/z 341 (M+H)⁺.

Example 185-chloro-2-methoxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 12A (39 mg, 0.15 mmol) and5-chloro-2-methoxybenzoic acid (41 mg, 0.22 mmol) were processed usingthe methods described in Example 13 to afford the title compound. MS(ESI) m/z 355 (M+H)⁺.

Example 191-hydroxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-naphthamide

The product of Example 12A (39 mg, 0.15 mmol) and 1-hydroxy-2-naphthoicacid (41 mg, 0.22 mmol) were processed using the methods described inExample 13 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm2.27 (s, 3H), 2.31 (s, 3H), 3.28 (s, 3H), 3.80 (t, 2H), 4.44 (t, 2H),7.36 (d, 1H), 7.53 (t, 1H), 7.61 (t, 1H), 7.86 (d, 1H), 8.06 (d, 1H),8.28 (d, 1H), 14.38 (s, 1H); MS (ESI) m/z 357 (M+H)⁺.

Example 204-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-1-naphthamide

The product of Example 12A (39 mg, 0.15 mmol) and 4-fluoro-1-naphthoicacid (42 mg, 0.22 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm2.25 (s, 3H) 2.28 (s, 3H) 3.26 (s, 3H) 3.74 (t, 2H) 4.41 (t, 2H)7.38-7.44 (m, 1H) 7.65-7.72 (m, 2H) 8.12 (d, 1H) 8.37-8.41 (m, 1H) 9.23(d, 1H) MS (ESI) m/z 359 (M+H)⁺.

Example 212-methoxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-4-(methylthio)benzamide

The product of Example 12A (39 mg, 0.15 mmol) and2-methoxy-4-methylsulfanylbenzoic acid (44 mg, 0.22 mmol) were processedusing the method described in Example 3 to afford the title compound. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.20 (s, 3H) 2.23 (s, 3H) 2.53 (s, 3H) 3.24(s, 3H) 3.68 (t, 2H) 3.81 (s, 3H) 4.29 (t, 2H) 6.83-6.87 (m, 1H)6.87-6.90 (m, 1H) 7.75 (d, 1H) MS (ESI) m/z 367 (M+H)⁺.

Example 222-chloro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-5-(methylthio)benzamide

The product of Example 12A (39 mg, 0.15 mmol) and2-chloro-5-methylsulfanylbenzoic acid (44 mg, 0.22 mmol) were processedusing the method described in Example 3 to afford the title compound. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.23 (s, 3H) 2.27 (s, 3H) 3.24 (s, 3H) 3.29(s, 3H) 3.69 (t, 2H) 4.33 (t, 2H) 7.30-7.33 (m, 1H) 7.39-7.42 (m, 1H)7.67 (d, 1H) MS (ESI) m/z 371 (M+H)⁺.

Example 23N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-4-(trifluoromethyl)nicotinamide

The product of Example 12A (0.30 g, 1.1 mmol) and4-trifluoromethylnicotinic acid (0.43 g, 2.2 mmol) were processed as inthe methods of Example 13. Purification by column chromatography (SiO₂,0-20% methanol/methylene chloride gradient) afforded 0.23 g (28%) of thetitle compound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 2.26 (s, 3H), 2.29 (s,3H), 3.30 (s, 3H), 3.72 (t, J=5.1 Hz, 2H), 4.33 (t, J=5.1 Hz, 2H), 7.59(d, J=5.1 Hz, 1H), 8.79 (d, J=5.1 Hz, 1H), 9.23 (s, 1H); MS (DCI/NH₃)m/z 360 (M+H)⁺. Anal. Calculated for C₁₅H₁₆F₃N₃O₂S: C, 50.13; H, 4.49;N, 11.69. Found: C, 50.12; H, 4.33; N, 11.75.

Example 242-hydroxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 12A (1.7 g, 9.4 mmol) and 2-hydroxybenzoic acid(1.6 g, 11 mmol) were processed using the method described in Example2B. Purification by column chromatography (SiO₂, 20-40% ethylacetate/hexanes gradient) afforded 0.91 g (32%) of the title compound.¹H NMR (CDCl₃, 300 MHz) δ ppm 2.26 (d, J=1.0 Hz, 3H), 2.29 (d, J=0.7 Hz,3H), 3.31 (s, 3H), 3.78-3.86 (m, 2H), 4.34 (t, J=5.1 Hz, 2H), 6.89 (dt,J=7.9, 7.0, 1.0 Hz, 1H), 6.95 (dd, J=8.1, 1.0 Hz, 1H), 7.37 (dt, J=7.7,1.9 Hz, 1H), 8.15 (dd, J=8.0, 1.9 Hz, 1H); MS (DCI/NH₃) m/z 307 (M+H)⁺.Anal. Calculated for C₁₅H₁₈N₂O₃S: C, 58.80; H, 5.92; N, 9.14. Found: C,58.60; H, 5.86; N, 9.01.

Example 252-(2-methoxyethoxy)-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamideExample 25A Methyl-2-(2-Methoxy-ethoxy)-benzoate

To a solution of triphenylphosphine (0.36 g, 1.40 mmol) in 10 mL of THFat 0° C. was added diisopropyl azodicarboxylate (275 μL, 1.40 mmol). Themixture was stirred for 0.5 hours and then methyl-2-hydroxybenzoate (400mg, 1.3 mmol) and 2-methoxyethanol (110 μl, 1.40 mmol) were added. Themixture was allowed to warm to ambient temperature and stirred for 16hours. The mixture was concentrated under reduced pressure and theresidue was used without purification. MS (DCI/NH₃) m/z 211 (M+H)⁺.

Example 25B 2-(2-Methoxy-ethoxy)-benzoic acid

A mixture of the product of Example 25A (0.27 g, 1.3 mmol) in 40%aqueous potassium hydroxide was stirred for 6 hours. The mixture wasthen diluted with water, made slightly acidic by the addition of 2 Naqueous HCl, and then extracted three times with ethyl acetate. Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated under reduced pressure to afford 0.25 g of the titlecompound.

Example 25C2-(2-Methoxy-ethoxy)-N-[3-(2-methoxyethyl)-4,5-dimethyl-3H-thiazol-2-ylidene]-benzamide

The product of Example 25B (0.25 g, 1.3 mmol) and the product of Example12A (0.28 g, 1.5 mmol) were processed using the methods described inExample 13. Purification by column chromatography (SiO₂, 30-60% ethylacetate/hexanes gradient) afforded 35 mg (7%) of the title compound. MS(DCI/NH₃) m/z 365 (M+H)⁺. Anal. Calculated for C₁₈H₂₄N₂O₄S.0.5H₂O: C,57.89; H, 6.75; N, 7.50. Found: C, 57.77; H, 6.59; N, 7.44.

Example 265-chloro-2-ethoxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 12A (97 mg, 0.52 mmol) and5-chloro-2-ethoxybenzoic acid (95 mg, 0.47 mmol) were processed usingthe methods described in Example 13 to afford the title compound. ¹H NMR(CDCl₃, 400 MHz) δ ppm 1.45 (t, J=6.9 Hz, 3H), 2.24 (s, 3H), 2.28 (s,3H), 3.31 (s, 3H), 3.78 (t, J=4.8 Hz, 2H), 4.15 (q, J=7.1 Hz, 2H), 4.45(s, 2H), 6.90 (d, J=8.6 Hz, 1H), 7.30 (dd, J=8.9, 2.8 Hz, 1H), 7.89 (d,J=2.8 Hz, 1H); MS (DCI/NH₃) m/z 369 (M+H)⁺. Anal. Calculated forC₁₇H₂₁ClN₂O₃S: C, 55.35; H, 5.74; N, 7.59. Found: C, 55.13; H, 5.59; N,7.54.

Example 272-ethoxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]nicotinamide

The product of Example 12A (0.40 g, 2.2 mmol) and 2-ethoxynicotinic acid(0.40 g, 2.4 mmol) were processed using the method described in Example2B. Purification by column chromatography (SiO₂, 0-30%methanol/methylene chloride gradient) afforded 0.34 g (45%) of the titlecompound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 1.45 (t, J=7.1 Hz, 3H), 2.23 (s,3H), 2.26 (s, 3H), 3.31 (s, 3H), 3.78 (t, J=5.3 Hz, 2H), 4.37 (d, J=4.7Hz, 2H), 4.52 (q, J=7.0 Hz, 2H), 6.91 (dd, J=7.5, 4.7 Hz, 1H), 8.21 (dd,J=4.7, 2.0 Hz, 1H), 8.32 (dd, J=7.5, 2.0 Hz, 1H); MS (DCI/NH₃) m/z 336(M+H)⁺. Anal. Calculated for C₁₆H₂₁N₃O₃S.0.2H₂O: C, 56.68; H, 6.36; N,12.39. Found: C, 56.65; H, 6.32; N, 12.38.

Example 282-chloro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]nicotinamide

A mixture of 2-chloronicotinic acid (0.42 g, 2.7 mmol) and1,1′-carbonyldiimidazole (0.43 g, 2.7 mmol) in 3 mL of ethyl acetate wasstirred at ambient temperature for 4 hours. The mixture was treated withwater (3 mL) and the product of Example 12A (0.45 g, 2.4 mmol) and thenheated at 65° C. for 13 hours. The mixture was cooled to ambienttemperature, diluted with ethyl acetate and the layers separated. Theorganic phase was washed with twice with water and then brine, driedover magnesium sulfate, filtered and concentrated under reducedpressure. The residue was recrystallized from methylene chloride andafforded 0.14 g (18%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 2.26 (s, 3H), 2.28 (s, 3H), 3.30 (s, 3H), 3.76 (t, J=5.1 Hz, 2H),4.36 (t, J=5.1 Hz, 2H), 7.28-7.32 (m, 1H), 8.28 (dd, J=7.5, 2.0 Hz, 1H),8.42 (dd, J=4.7, 2.0 Hz, 1H); MS (DCI/NH₃) m/z 326 (M+H)⁺. Anal.Calculated for C₁₄H₁₆ClN₃O₂5: C, 51.61; H, 4.95; N, 12.90. Found: C,51.57; H, 4.76; N, 12.74.

Example 29N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-(trifluoromethoxy)benzamide

A mixture of 2-trifluoromethoxybenzoyl chloride (0.59 g, 2.6 mmol) andthe product of Example 12A were processed using the method described inExample 11 to afford the title compound. ¹H NMR (CDCl₃, 300 MHz) δ ppm2.24 (s, 3H), 2.28 (s, 3H), 3.29 (s, 3H), 3.76 (t, J=4.9 Hz, 2H), 4.45(t, J=4.7 Hz, 2H), 7.27-7.39 (m, 2H), 7.46 (td, J=7.7, 1.9 Hz, 1H), 8.06(dd, J=7.6, 1.9 Hz, 1H); Anal. Calculated for C₁₆H₁₇F₃N₂O₃S: C, 51.33;H, 4.58; N, 7.48. Found: C, 51.29; H, 4.40; N, 7.37.

Example 305-bromo-2-ethoxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 12A (0.20 g, 1.1 mmol) and5-bromo-2-ethoxybenzoyl chloride (0.28 g, 1.1 mmol) were processed usingthe method described in Example 11. Purification by columnchromatography (SiO₂, 30-60% ethyl acetate/hexanes gradient) afforded149 mg (38%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 1.46(t, J=7.0 Hz, 3H), 2.25 (s, 3H), 2.29 (s, 3H), 3.31 (s, 3H), 3.79 (t,J=4.6 Hz, 2H), 4.09-4.23 (m, 2H), 4.44-4.61 (m, 2H), 6.85 (d, J=8.8 Hz,1H), 7.42-7.48 (m, 1H), 8.02 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 415(M+H)⁺. Anal. Calculated for C₁₇H₂₁BrN₂O₃S: C, 49.40; H, 5.12; N, 6.78.Found: C, 49.68; H, 5.03; N, 6.71.

Example 31N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-(trifluoromethyl)benzamide

The product of Example 12A (0.50 g, 2.7 mmol) and2-trifluoromethylbenzoyl chloride (0.62 g, 3.0 mmol) were processedusing the method described in Example 11. Purification by columnchromatography (SiO₂, 20-40% ethyl acetate/hexanes gradient) afforded0.43 g (44%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 2.26(s, 3H), 2.28 (s, 3H), 3.29 (s, 3H), 3.72 (t, J=4.7 Hz, 2H), 4.41 (t,J=4.6 Hz, 2H), 7.45-7.62 (m, 2H), 7.71 (d, J=7.1 Hz, 1H), 7.86 (d, J=7.1Hz, 1H); MS (DCI/NH₃) m/z 359 (M+H)⁺. Anal. Calculated forC₁₆H₁₇F₃N₂O₂S: C, 53.62; H, 4.78; N, 7.82. Found: C, 53.58; H, 4.51; N,7.70.

Example 322-iodo-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 12A (0.25 g, 1.3 mmol) and 2-iodobenzoyl chloride(0.37 g, 1.4 mmol) were processed using the method described in Example11. Purification by preparative HPLC on a Waters Symmetry C8 column (40mm×100 mm, 7 μm particle size) using a gradient of 20% to 95%acetonitrile:0.1% aqueous TFA over 12 minutes (15 minutes run time) at aflow rate of 70 mL/min afforded 0.12 g (23%) of the title compound. ¹HNMR (CDCl₃, 300 MHz) δ ppm 2.30 (s, 3H), 2.31 (s, 3H), 3.29 (s, 3H),3.72 (t, J=4.7 Hz, 2H), 4.41 (t, J=4.6 Hz, 2H), 7.45-7.62 (m, 2H), 7.71(d, J=7.1 Hz, 1H), 7.86 (d, J=7.1 Hz, 1H); MS (DCI/NH₃) m/z 417 (M+H)⁺.

Example 332-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

The product of Example 12A (0.25 g, 1.3 mmol) and2-fluoro-5-trifluoromethylbenzoyl chloride (0.32 g, 1.4 mmol) wereprocessed using the method described in Example 11. Purification bypreparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μmparticle size) usinga gradient of 20% to 95% acetonitrile:0.1% aqueousTFA over 12 minutes (15 minutes run time) at a flow rate of 70 mL/minafforded 70 mg (14%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 2.29 (s, 3H), 2.31 (s, 3H), 3.33 (s, 3H), 3.73-3.89 (m, 2H),4.44-4.57 (m, 2H), 7.18-7.24 (m, 1H), 7.68 (d, J=9.2 Hz, 1H), 8.38 (d,J=6.8 Hz, 1H); MS (DCI/NH₃) m/z 377 (M+H)⁺. Anal. Calculated forC₁₆H₁₆F₄N₂O₂S.0.1H₂O: C, 51.06; H, 4.28; N, 7.44. Found: C, 50.54; H,4.05; N, 7.27.

Example 342-bromo-5-methoxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 12A (0.20 g, 1.1 mmol) and2-bromo-5-methoxybenzoic acid (0.25 g, 1.1 mmol) were processed usingthe methods described in Example 13. Purification by preparative

HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size)using a gradient of 20% to 95% acetonitrile:0.1% aqueous TFA over 12minutes (15 minutes run time) at a flow rate of 70 mL/min afforded 0.13g (29%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 2.27 (s,3H), 2.29 (s, 3H), 3.30 (s, 3H), 3.80 (t, J=4.7 Hz, 2H), 3.83 (s, 3H),4.50-4.59 (m, 2H), 6.82 (dd, J=8.8, 3.1 Hz, 1H), 7.44 (d, J=3.1 Hz, 1H),7.50 (d, J=8.8 Hz, 1H); MS (DCI/NH₃) m/z 401 (M+H)⁺. Anal. Calculatedfor C₁₆H₁₉BrN₂O₃S: C, 48.13; H, 4.80; N, 7.02. Found: C, 47.88; H, 4.55;N, 6.89.

Example 355-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-(trifluoromethyl)benzamide

The product of Example 12A (0.20 g, 1.1 mmol) and5-fluoro-2-trifluoromethylbenzoyl chloride (0.18 mL, 1.2 mmol) wereprocessed using the method described in Example 11. Purification bypreparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μmparticle size) using a gradient of 20% to 95% acetonitrile:0.1% aqueousTFA over 12 minutes (15 minutes run time) at a flow rate of 70 mL/minafforded 43 mg (11%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 2.27 (s, 3H), 2.29 (s, 3H), 3.30 (s, 3H), 3.65-3.76 (m, 2H),4.37-4.48 (m, 2H), 7.13-7.20 (m, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.71 (dd,J=9.2, 5.4 Hz, 1H); MS (DCI/NH₃) m/z 377 (M+H)⁺. Anal. Calculated forC₁₆H₁₆F₄N₂O₂S.0.3H₂O: C, 50.34; H, 4.38; N, 7.34. Found: C, 49.95; H,4.02; N, 7.09.

Example 36N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2,5-bis(trifluoromethyl)benzamide

The product of Example 12A (0.20 g, 1.1 mmol) and2,5-bis-trifluoromethylbenzoyl chloride (0.33 g, 1.2 mmol) wereprocessed using the method described in Example 11. Purification bypreparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μmparticle size) using a gradient of 20% to 95% acetonitrile:0.1% aqueousTFA over 12 minutes (15 minutes run time) at a flow rate of 70 mL/minafforded 0.14 g (31%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 2.27 (s, 3H), 2.29 (s, 3H), 3.30 (s, 3H) 3.71 (t, J=4.9 Hz, 2H) 4.36(t, J=5.1 Hz, 2H) 7.72-7.77 (m, 1H) 7.82-7.87 (m, 1H) 8.15 (s, 1H); MS(DCI/NH₃) m/z 427 (M+H)⁺. Anal. Calculated for C₁₇H₁₆F₆N₂O₂S: C, 47.89;H, 3.78; N, 6.57. Found: C, 47.49; H, 3.42; N, 6.38.

Example 372-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-6-(trifluoromethyl)benzamide

The product of Example 12A (0.20 g, 1.1 mmol) and2-fluoro-6-trifluoromethylbenzoyl chloride (0.17 mL, 1.2 mmol) wereprocessed using the method described in Example 11. Purification bypreparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μmparticle size) using a gradient of 20% to 95% acetonitrile:0.1% aqueousTFA over 12 minutes (15 minutes run time) at a flow rate of 70 mL/minafforded 0.13 g (32%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 2.27 (s, 3H), 2.28 (s, 3H), 3.27 (s, 3H), 3.69 (t, J=4.9 Hz, 2H),4.37 (t, J=4.6 Hz, 2H), 7.28-7.33 (m, 1H), 7.38-7.50 (m, 2H); MS(DCI/NH₃) m/z 377 (M+H)⁺. Anal. Calculated for C₁₆H₁₆F₄N₂O₂S: C, 51.06;H, 4.28; N, 7.44. Found: C, 50.98; H, 4.07; N, 7.36.

Example 382-chloro-6-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 12A (0.20 g, 1.1 mmol) and2-chloro-6-fluorobenzoyl chloride (0.23 g, 1.2 mmol) were processedusing the method described in Example 11. Purification by preparativeHPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size)using a gradient of 20% to 95% acetonitrile:0.1% aqueous TFA over 12minutes (15 minutes run time) at a flow rate of 70 mL/min afforded 66 mg(18%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 2.26 (s, 3H),2.27 (s, 3H), 3.28 (s, 3H), 3.73 (t, J=4.9 Hz, 2H), 4.35 (t, J=4.7 Hz,2H), 6.97-7.05 (m, 1H), 7.19-7.24 (m, 2H); MS (DCI/NH₃) m/z 343 (M+H)⁺.Anal. Calculated for C₁₅H₁₆ClFN₂O₂S.0.2C₂HF₃O₂: C, 50.59; H, 4.47; N,7.66. Found: C, 50.70; H, 4.34; N, 7.55.

Example 393-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-(trifluoromethyl)benzamide

The product of Example 12A (0.335 g, 1.9 mmol) and3-fluoro-2-trifluoromethylbenzoyl chloride (0.47 g, 2.1 mmol) wereprocessed using the method described in Example 11. Purification bypreparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μmparticle size) using a gradient of 20% to 95% acetonitrile:0.1% aqueousTFA over 12 minutes (15 minutes run time) at a flow rate of 70 mL/minafforded 0.14 g (20%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 2.25 (d, J=0.7 Hz, 3H), 2.27 (s, 3H), 3.28 (s, 3H), 3.68 (t, J=5.1Hz, 2H), 4.31 (t, J=5.1 Hz, 2H), 7.18 (dd, J=11.0, 8.3 Hz, 1H),7.38-7.42 (m, 1H), 7.52 (td, J=8.0, 5.1 Hz, 1H); MS (DCI/NH₃) m/z 377(M+H)⁺. Anal. Calculated for C₁₆H₁₆F₄N₂O₂S: C, 51.06; H, 4.28; N, 7.44.Found: C, 51.15; H, 3.96; N, 7.38.

Example 402-chloro-5-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 12A (0.20 g, 1.1 mmol) and2-chloro-5-fluorobenzoyl chloride (0.23 g, 1.2 mmol) were processedusing the method described in Example 11. Purification by preparativeHPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size)using a gradient of 20% to 95% acetonitrile:0.1% aqueous TFA over 12minutes (15 minutes run time) at a flow rate of 70 mL/min afforded 17 mg(4%) of the title compound. ¹H NMR (DMSO-d₆, 500 MHz) δ ppm 2.23 (s,3H), 2.26 (s, 3H), 3.22 (s, 3H), 3.68 (t, J=5.3 Hz, 2H), 4.33 (t, J=5.3Hz, 2H), 7.30 (td, J=8.4, 3.1 Hz, 1H), 7.52 (dd, J=8.9, 5.2 Hz, 1H),7.64 (dd, J=9.1, 3.3 Hz, 1H); MS (DCI/NH₃) m/z 343 (M+H)⁺. Anal.Calculated for C₁₅H₁₆ClFN₂O₂S.0.1C₂HF₃O₂: C, 51.54; H, 4.58; N, 7.91.Found: C, 51.68; H, 4.35; N, 7.95.

Example 41N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide

The product of Example 12A (1.5 g, 8.0 mmol) and2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.77 g, 5.4 mmol) wereprocessed using the methods described in Example 13. Recrystallizationfrom ethyl acetate afforded 0.99 g (60%) of the title compound. ¹H NMR(DMSO-d₆, 300 MHz) δ ppm 1.16 (s, 6H), 1.23 (s, 6H), 1.44 (s, 1H), 2.13(s, 3H), 2.19 (s, 3H), 3.24 (s, 3H), 3.61 (t, J=5.4 Hz, 2H), 4.21 (t,J=5.4 Hz, 2H); MS (DCI/NH₃) m/z 311 (M+H)⁺. Anal. Calculated forC₁₆H₂₆N₂O₂S: C, 61.92; H, 8.44; N, 9.02. Found: C, 61.89; H, 8.38; N,8.81.

Example 42N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-methylpentanamide

The product of Example 12A (39 mg, 0.15 mmol) and 2-methylvaleric acid(26 mg, 0.22 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (DMSO-d₆, 300 MHz) δ ppm 0.85 (t,3H) 1.09 (d, 3H) 1.20-1.28 (m, 2H) 1.32-1.40 (m, 1H) 1.59-1.67 (m, 1H)2.19 (s, 3H) 2.22 (s, 3H) 2.52-2.57 (m, 1H) 3.24 (s, 3H) 3.63 (t, 2H)4.26-4.33 (m, 2H) MS (ESI) m/z 285 (M+H)⁺.

Example 43N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2,2-dimethylbutanamide

The product of Example 12A (39 mg, 0.15 mmol) and 2,2-dimethylbutyricacid (26 mg, 0.22 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (DMSO-d₆, 300 MHz) δ ppm0.72 (t, 3H) 1.11 (s, 6H) 1.53-1.59 (m, 2H) 2.15 (s, 3H) 2.19 (s, 3H)3.24 (s, 3H) 3.63 (t, 2H) 4.22 (t, 2H) MS (ESI) m/z 285 (M+H)⁺.

Example 442-ethyl-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]butanamide

The product of Example 12A (39 mg, 0.15 mmol) and 2-ethylbutyric acid(26 mg, 0.22 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (DMSO-d₆, 300 MHz) δ ppm 0.80 (t,6H) 1.48 (s, 2H) 1.56-1.65 (m, 2H) 2.19 (s, 3H) 2.23 (s, 3H) 2.27-2.33(m, 1H) 3.23 (s, 3H) 3.63 (t, 2H) 4.24-4.33 (m, 2H) MS (ESI) m/z 285(M+H)⁺.

Example 45N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]cyclohexanecarboxamide

The product of Example 12A (39 mg, 0.15 mmol) and cyclohexanecarboxylicacid (28 mg, 0.22 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (DMSO-d₆, 300 MHz) δ ppm1.23-1.32 (m, 2H) 1.34-1.43 (m, 2H) 1.58-1.65 (m, 1H) 1.67-1.74 (m, 2H)1.83-1.89 (m, 2H) 2.19 (s, 3H) 2.23 (s, 3H) 2.35-2.42 (m, 1H) 3.24 (s,3H) 3.64 (t, 2H) 4.31 (t, 3H) MS (ESI) m/z 297 (M+H)⁺.

Example 46N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-1-methylcyclohexanecarboxamide

The product of Example 12A (0.30 g, 1.1 mmol) and1-methylcyclohexane-carboxylic acid (0.32 g, 2.2 mmol) were processedusing the methods described in Example 13. Purification by columnchromatography (SiO₂, 30-50% ethyl acetate/hexanes gradient) afforded 80mg (23%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 1.16 (s,3H), 1.19-1.58 (m, 10H), 2.18 (s, 3H), 2.20 (s, 3H), 3.30 (s, 3H), 3.69(t, J=5.3 Hz, 2H), 4.19-4.31 (m, 2H); MS (DCI/NH₃) m/z 311 (M+H)⁺. Anal.Calculated for C₁₆H₂₆N₂O₂S: C, 61.90; H, 8.44; N, 9.02. Found: C, 61.86;H, 8.80; N, 9.02.

Example 47cis-N-[(2Z)-3-(2-Methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-methylcyclohexanecarboxamide

The product of Example 12A (0.30 g, 1.1 mmol) and(cis)-2-methyl-cyclohexanecarboxylic acid (0.32 g, 2.2 mmol) wereprocessed using the methods described in Example 13. Purification bycolumn chromatography (SiO₂, 30-50% ethyl acetate/hexanes gradient)afforded 0.24 g (68%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 0.85 (d, J=7.1 Hz, 3H), 1.36-1.84 (m, 8H), 2.17 (s, 3H), 2.20 (s,3H), 2.31-2.42 (m, 1H), 2.53-2.65 (m, 1H), 3.29 (s, 3H), 3.69 (t, J=4.2Hz, 2H), 4.17-4.29 (m, 2H); MS (DCI/NH₃) m/z 311 (M+H)⁺. Anal.Calculated for C₁₆H₂₆N₂O₂S: C, 61.90; H, 8.44; N, 9.02. Found: C, 62.15;H, 8.70; N, 8.73.

Example 48N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-4-methylcyclohexanecarboxamide

The product of Example 12A (39 mg, 0.15 mmol) and4-methylcyclohexanecarboxylic acid (31 mg, 0.22 mmol) were processedusing the methods described in Example 13 to afford the title compound.¹H NMR (DMSO-d₆, 300 MHz) δ ppm 0.84-0.89 (m, 3H) 1.15-1.23 (m, 2H)1.47-1.56 (m, 4H) 1.95-2.03 (m, 2H) 2.19 (s, 3H) 2.23 (s, 3H) 3.24 (s,3H) 3.60-3.67 (m, 2H) 4.26-4.36 (m, 4H) MS (ESI) m/z 311 (M+H)⁺.

Example 49N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]cycloheptanecarboxamide

The product of Example 12A (39 mg, 0.15 mmol) and cycloheptanecarboxylicacid (31 mg, 0.22 mmol) were processed using the methods described inExample 13 to afford the title compound. ¹H NMR (DMSO-d₆, 300 MHz) δ ppm1.45-1.52 (m, 4H) 1.54-1.56 (m, 2H) 1.60-1.70 (m, 4H) 1.85-1.92 (m, 2H)2.19 (s, 3H) 2.23 (s, 3H) 2.55-2.61 (m, 1H) 3.24 (s, 3H) 3.61-3.66 (m,2H) 4.27-4.34 (m, 2H) MS (ESI) m/z 311 (M+H)⁺.

Example 50(1S)—N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]spiro[2.5]octane-1-carboxamide

The product of Example 12A and (1S)-spiro[2.5]octane-1-carboxylic acid(Bennani, Y. L., et al. US 20042043961) were processed using the methodsdescribed in Example 13 to provide the title compound. MS (DCI/NH₃) m/z323 (M+H)⁺.

Example 51(2R)—N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-propylhex-4-ynamide

The product of Example 12A (0.30 g, 1.1 mmol) and(2R)-propyl-hex-4-ynoic acid (0.35 g, 2.2 mmol) were processed using themethods described in Example 13. Purification by column chromatography(SiO₂, 20-30% ethyl acetate/hexanes gradient) afforded 0.30 g (82%) ofthe title compound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 0.90 (t, J=7.5 Hz,3H), 1.27-1.39 (m, 2H), 1.62-1.72 (m, 2H), 1.75 (t, J=2.4 Hz, 3H), 2.19(s, 3H), 2.22 (s, 3H), 2.31-2.74 (m, 3H), 3.29 (s, 3H), 3.65-3.75 (m,2H), 4.16-4.33 (m, 2H); MS (DCI/NH₃) m/z 323 (M+H)⁺. Anal. Calculatedfor C₁₇H₂₆N₂O₂S: C, 63.32; H, 8.13; N, 8.69. Found: C, 63.12; H, 8.35;N, 8.51.

Example 52(1S,3R,5S)—N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-3,5-dimethylcyclohexanecarboxamide

The product of Example 12A (0.30 g, 1.1 mmol) and(1S,3R,5S)-dimethylcyclohexanecarboxylic acid (0.35 g, 2.2 mmol) wereprocessed using the methods described in Example 13. Purification bycolumn chromatography (SiO₂, 20-40% ethyl acetate/hexanes gradient)afforded 0.12 g (33%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 0.91 (s, 3H), 0.92-0.94 (m, 3H), 1.01-1.13 (m, 2H), 1.61-1.69 (m,3H), 1.90-2.00 (m, 3H), 2.19 (s, 3H), 2.21-2.25 (m, 3H), 2.26-2.30 (m,1H), 3.30 (s, 3H), 3.71 (t, J=5.3 Hz, 2H), 4.19-4.44 (m, 2H); MS(DCI/NH₃) m/z 325 (M+H)⁺. Anal. Calculated for C₁₇H₂₈N₂O₂S: C, 62.93; H,8.70; N, 8.63. Found: C, 63.29; H, 8.91; N, 8.71.

Example 53(9R,1R,8S)—N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]bicyclo[6.1.0]nonane-9-carboxamide

(endo)-Bicyclo[6.1.0]nonane-9-carboxylic acid (0.38 g, 2.2 mmol,Bennani, Y. L., et al., US2004077617) and the product of Example 12A(0.30 g, 1.1 mmol) were processed using the methods described in Example13. Purification by column chromatography (SiO₂, 20-35% ethylacetate/hexanes gradient) afforded 0.27 g (72%) of the title compound.¹H NMR (CDCl₃, 300 MHz) δ ppm 1.03-1.20 (m, 1H), 1.29-1.51 (m, 6H),1.52-1.77 (m, 6H), 2.07 (dd, J=14.1, 2.9 Hz, 2H), 2.17 (s, 3H), 2.20 (s,3H), 3.31 (s, 3H), 3.70 (t, J=4.9 Hz, 2H), 4.20-4.30 (m, 2H); MS(DCI/NH₃) m/z 337 (M+H)⁺. Anal. Calculated for C₁₈H₂₈N₂O₂S: C, 64.25; H,8.39; N, 8.32. Found: C, 64.06; H, 8.54; N, 8.22.

Example 54(9S,1R,8S)—N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]bicyclo[6.1.0]nonane-9-carboxamide

(exo)-Bicyclo[6.1.0]nonane-9-carboxylic acid (0.38 g, 2.2 mmol, Bennani,Y. L., et al., US2004077617) and the product of Example 12A (0.30 g, 1.1mmol) were processed using the methods described in Example 13.Purification by column chromatography (SiO₂, 20-30% ethylacetate/hexanes gradient) afforded 70 mg (19%) of the title compound. ¹HNMR (CDCl₃, 300 MHz) δ ppm 1.17-1.29 (m, 2H), 1.34-1.49 (m, 6H),1.57-1.76 (m, 6H), 1.95-2.04 (m, 1H), 2.15 (s, 3H), 2.20 (s, 3H), 3.30(s, 3H), 3.70 (t, J=5.3 Hz, 2H), 4.24 (t, J=5.3 Hz, 2H); MS (DCI/NH₃)m/z 337 (M+H)⁺. Anal. Calculated for C₁₈H₂₈N₂O₂S: C, 64.25; H, 8.39; N,8.32. Found: C, 64.33; H, 8.52; N, 8.23.

Example 55(1R,6R,7R)—N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-1-methylbicyclo[4.1.0]heptane-7-carboxamide

The product of Example 12A (0.30 g, 1.1 mmol) and1-methylbicyclo[4.1.0]heptane-7-carboxylic acid (0.35 g, 2.2 mmol,Bennani, Y. L., et al., US2004077617) were processed using the methodsdescribed in Example 13. Purification by column chromatography (SiO₂,20-35% ethyl acetate/hexanes gradient) afforded 40 mg (11%) of the titlecompound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 1.15-1.42 (m, 7H), 1.58-1.72 (m,3H), 1.77 (d, J=5.4 Hz, 1H), 1.84-2.04 (m, 2H), 2.15 (s, 3H), 2.19 (s,3H), 3.28-3.33 (m, 3H), 3.69 (t, J=5.3 Hz, 2H), 4.12-4.39 (m, 2H); MS(DCI/NH₃) m/z 323 (M+H)⁺. Anal. Calculated for C₁₇H₂₆N₂O₂S: C, 63.32; H,8.13; N, 8.69. Found: C, 63.35; H, 8.3; N, 8.56.

Example 57 2,2,3,3-Tetramethylcyclopropanecarboxylic acid[4,5-dimethyl-3-(2-phenoxy-ethyl)-3H-thiazol-2-ylidene]-amide Example57A 4,5-Dimethyl-3-(2-phenoxy-ethyl)-3H-thiazol-2-ylideneaminehydrobromide

A mixture of 4,5-dimethylthiazol-2-ylamine (1.0 g, 7.8 mmol) and(2-bromo-ethoxy)benzene (1.9 g, 9.4 mmol) were heated neat to 85° C. for19 hours. The mixture was cooled to ambient temperature and the residuewas crystallized from isopropanol. The solid was collected by filtrationand dried under vacuum to afford 1.3 g (50%) of the title compound. MS(DCI/NH₃) m/z 249 (M+H)⁺.

Example 57B 2,2,3,3-Tetramethylcyclopropanecarboxylic acid[4,5-dimethyl-3-(2-phenoxy-ethyl)-3H-thiazol-2-ylidene]-amide

The product of Example 57A (0.40 g, 1.2 mmol) and2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.19 g, 1.3 mmol) wereprocessed using the methods described in Example 13. Purification bycolumn chromatography (SiO₂, 20-40% ethyl acetate/hexanes gradient)afforded 0.14 g (34%) of the title compound. ¹H NMR (CDCl₃, 500 MHz) δppm 1.22 (s, 6H), 1.32-1.35 (m, 6H), 1.56 (s, 1H), 2.15 (s, 3H), 2.27(s, 3H), 4.32 (t, J=5.5 Hz, 2H), 4.44 (t, J=5.3 Hz, 2H), 6.90 (d, J=8.1Hz, 2H), 6.95 (t, J=7.3 Hz, 1H), 7.25-7.29 (m, 2H); MS (DCI/NH₃) m/z 373(M+H)⁺. Anal. Calculated for C₂₁H₂₈N₂O₂S: C, 67.71; H, 7.58; N, 7.52.Found: C, 67.31; H, 7.70; N, 7.30.

Example 58N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2,2-dimethyltetrahydro-2H-pyran-4-carboxamide

A mixture of the product of Example 12A (150 mg, 0.56 mmol),2,2-dimethyl-tetrahydro-pyran-4-carboxylic acid (127 mg, 0.56 mmol),N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (133 mg,0.70 mmol), 1-hydroxybenzotriazole (94.5 mg, 0.70 mmol) andtriethylamine (312 μL, 2.24 mmol) in 5 mL of THF were stirred overnightat room temperature. The reaction mixture was diluted with ethyl acetateand washed with 1 M aqueous NaHCO₃ and brine. The organic extract wasdried (Na₂SO₄), filtered and concentrated. Purification of the residueby chromatography afforded the title compound: ¹H NMR (400 MHz, DMSO-d₆)δ1.13 (s, 3H) 1.16 (s, 3H) 1.33-1.53 (m, 2H) 1.67-1.77 (m, 2H) 2.16 (s,3H) 2.20 (s, 3H) 2.59-2.72 (m, 1H) 3.24 (s, 3H) 3.53-3.61 (m, 2H) 3.63(t, J=5.1 Hz, 2H) 4.24 (t, J=5.4 Hz, 2H); MS (ESI+) m/z 327 (M+H)⁺.

Example 592,2,3,3-tetrafluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-1-methylcyclobutanecarboxamide

The product of 12A (0.30 g, 1.6 mmol) and2,2,3,3-tetrafluoro-1-methyl-cyclobutanecarborboxylic acid (0.37 g, 1.8mmol) were processed using the methods described in Example 13.Purification by column chromatography (SiO₂, 30-45% ethylacetate/hexanes gradient) afforded 0.15 g (27%) of the title compound.¹H NMR (CDCl₃, 300 MHz) δ ppm 1.59 (s, 3H), 2.23 (s, 3H), 2.25 (s, 3H),2.29-2.43 (m, 1H), 3.29 (s, 3H), 3.31-3.46 (m, 1H), 3.70 (t, J=5.1 Hz,2H), 4.26-4.48 (m, 2H); MS (DCI/NH₃) m/z 355 (M+H)⁺. Anal. Calculatedfor C₁₄H₁₈F₄N₂O₂S: C, 47.45; H, 5.12; N, 7.91. Found: C, 47.41; H, 5.04;N, 7.81.

Example 601-hydroxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]cyclohexanecarboxamide

Commercially available 1-hydroxy-cyclohexanecarboxylic acid and theproduct of Example 12A were processed using the method described inExample 58 to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.09-1.32 (m, 1H), 1.36-1.68 (m, 7H), 1.72-1.88 (m, 2H), 2.18 (s, 3H),2.22 (s, 3H), 3.23 (s, 3H), 3.64 (t, J=5.3 Hz, 2H), 4.29 (t, J=5.4 Hz,2H), 4.34 (s, 1H); MS (ESI⁺) m/z 335 (M+Na)⁺; Anal. Calculated forC₁₅H₂₄N₂O₃S: C, 57.66; H, 7.74; N, 8.97. Found: C, 57.76; H, 7.80; N,8.88.

Example 611-({[(2Z)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)cyclohexylpropionate

Propionyloxy-cyclohexanecarboxylic acid (Hartmann, Willy et al.,Synthesis (1989), 4, 272-4) and the product from Example 12A wereprocessed using the method described in Example 58 to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.03 (t, J=7.5 Hz, 3H),1.15-1.34 (m, 1H), 1.36-1.66 (m, 5H), 1.75 (td, J=13.1, 4.1 Hz, 2H),2.01-2.13 (m, 2H), 2.16 (s, 3H), 2.20 (s, 3H), 2.32 (q, J=7.5 Hz, 2H),3.22 (s, 3H), 3.58 (t, J=5.4 Hz, 2H), 4.19 (t, J=5.4 Hz, 2H); MS (ESI⁺)m/z 369 (M+H)⁺; Anal. Calculated for C₁₈H₂₈N₂O₄S: C, 58.67; H, 7.66; N,7.60. Found: C, 58.46; H, 7.64; N, 7.75.

Example 62N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 62A 2,2,3,3-Tetramethylcyclopropanecarboxylic acidbenzothiazol-2-ylamide

A mixture of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.50 g, 3.5mmol) and benzothiazol-2-ylamine (0.58 g, 3.9 mmol) were processed as inExample 9A. Purification by column chromatography (SiO₂, 20-40% ethylacetate/hexanes gradient) afforded 0.26 g (27%) of the title compound.¹H NMR (CDCl₃, 300 MHz) δ ppm 1.22-1.27 (m, 6H), 1.36 (s, 6H), 1.67 (s,1H), 2.07-2.18 (m, 2H), 3.34 (s, 3H), 3.41 (t, J=5.8 Hz, 2H), 4.39-4.53(m, 2H), 7.20-7.26 (m, 1H), 7.37-7.42 (m, 2H), 7.60 (d, J=7.5 Hz, 1H);MS (DCI/NH₃) m/z 275 (M+H)⁺.

Example 62B 2,2,3,3-Tetramethylcyclopropanecarboxylic acid[3-(2-methoxyethyl)-3H-benzothiazol-2-ylidene]-amide

The product of Example 62A (0.12 g, 0.43 mmol), 2-bromoethyl methylether (0.44 mL, 4.7 mmol) and potassium hydroxide (56 mg, 1.0 mmol) wereprocessed using the method described in Example 1B. Purification bycolumn chromatography (SiO₂, 20-50% ethyl acetate/hexanes gradient)afforded 12 mg (8%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δ ppm1.25 (s, 6H), 1.36 (s, 6H), 1.66 (s, 1H), 3.34 (s, 3H), 3.79 (t, J=5.6Hz, 2H), 4.53 (t, J=5.6 Hz, 2H), 7.21-7.25 (m, 1H), 7.37-7.42 (m, 2H),7.58 (d, J=7.8 Hz, 1H); MS (DCI/NH₃) m/z 371 (M+H)⁺. Anal. Calculatedfor C₁₈H₂₄N₂O₂S: C, 65.03; H, 7.28; N, 8.43. Found: C, 64.94; H, 7.10;N, 8.40.

Example 63N-[(2Z)-3-(3-methoxypropyl)-1,3-benzothiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 63A 3-(3-Methoxy-propyl)-3H-benzothiazol-2-ylideneaminehydrobromide

Benzothiazol-2-ylamine (1.0 g, 6.6 mmol) and 1-bromo-3-methoxy-propane(1.2 g, 7.9 mmol) were processed using the method described in Example12A. Recrystallization from ethyl acetate provided 1.7 g (89%) of thetitle compound. ¹H NMR (DMSO-d₆, 300 MHz) δ ppm 1.90-2.02 (m, 2H), 3.18(s, 3H), 3.39 (t, J=5.9 Hz, 2H), 4.31 (t, J=7.1 Hz, 2H), 7.37-7.48 (m,1H), 7.53-7.69 (m, 2H), 8.00 (dd, J=8.0, 0.8 Hz, 1H), 10.08 (s, 1H); MS(DCI/NH₃) m/z 233 (M+H)⁺.

Example 63B 2,2,3,3-Tetramethylcyclopropanecarboxylic acid[3-(3-methoxy-propyl)-3H-benzothiazol-2-ylidene)-amide

The product of Example 63A (0.40 g, 1.3 mmol) and2,2,3,3-Tetramethylcyclopropanecarboxylic acid (0.19 g, 1.3 mmol) wereprocessed using the methods described in Example 13. Purification bycolumn chromatography (SiO₂, 20-30% ethyl acetate/hexanes gradient)afforded 0.32 g (70%) of the title compound. ¹H NMR (CDCl₃, 300 MHz) δppm 1.26 (s, 6H), 1.36 (s, 6H), 1.64 (br s, 1H), 1.71 (s, 1H), 3.87 (s,3H), 7.27-7.32 (m, 2H), 7.40-7.47 (m, 1H), 7.62 (d, J=7.5 Hz, 1H); MS(DCI/NH₃) m/z 289 (M+H)⁺. Anal. Calculated for C₁₆H₂₀N₂O₂S: C, 65.86; H,7.56; N, 8.08. Found: C, 65.54; H, 7.65; N, 7.81.

Example 64N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-3-phenylpropanamideExample 64A 3-(2-Methoxyethyl)-3H-benzothiazol-2-ylideneaminehydrobromide

Benzothiazol-2-ylamine (10.0 g, 66.6 mmol) and 2-bromoethyl methyl ether(9.39 mL, 99.9 mmol) were combined and heated at 85° C. for 6 hours. Thedark solid was triturated with EtOH then filtered and dried under vacuumto afford the title compound (15.8 g, 82%). ¹H NMR (DMSO-d₆, 300 MHz) δppm 3.23 (s, 3H), 3.69 (t, J=5.1 Hz, 2H), 4.51 (t, J=5.1 Hz, 2H), 7.42(dt, J=1.0, 8.0 Hz, 1H), 7.56 (m, 1H), 7.72 (d, J=8.0 Hz, 1H), 8.00 (dd,J=1.1, 8.0 Hz, 1H), 10.16 (br s, 2H); MS (DCI/NH₃) m/z 209 (M+H)⁺.

Example 64BN-[3-(2-Methoxyethyl)-3H-benzothiazol-2-ylidene]-3-phenylpropionamide

The product of Example 64A (39 mg, 0.14 mmol) and hydrocinnamic acid (26mg, 0.17 mmol) were processed using the method described in Example 3 toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.77-2.85 (m,2H) 2.92-3.05 (m, 2H) 3.19-3.25 (m, 3H) 3.76 (t, 2H) 4.52 (t, 2H)7.08-7.19 (m, 1H) 7.22-7.37 (m, 5H) 7.41-7.53 (m, 1H) 7.59-7.74 (m, 1H)7.75-8.03 (m, 1H); MS(ESI) m/z 341 (M+H)⁺.

Example 65(2S)—N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2-phenylbutanamide

The product of Example 64A (39 mg, 0.14 mmol) and(S)-(+)-2-phenylbutyric acid (26 mg, 0.17 mmol) were processed using themethod described in Example 3 to afford the title compound. ¹H NMR (500MHz, DMSO-d₆) δ ppm 0.89 (t, 3H) 1.69-1.89 (m, 1H) 2.04-2.23 (m, 1H)3.11-3.20 (m, 3H) 3.57-3.76 (m, 3H) 4.54 (t, 2H) 7.17-7.23 (m, 1H)7.27-7.41 (m, 5H) 7.43-7.53 (m, 1H) 7.61-7.71 (m, 1H) 7.74-7.88 (m, 1H);MS(ESI) m/z 355 (M+H)⁺.

Example 66N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-4-thien-2-ylbutanamide

The product of Example 64A (39 mg, 0.14 mmol) and 4-(2-thienyl)butyricacid (29 mg, 0.17 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.86-2.08 (m, 2H) 2.55 (t, 2H) 2.87 (t, 2H) 3.17-3.24 (m, 3H) 3.72 (t,2H) 4.54 (t, 2H) 6.83-6.89 (m, 1H) 6.90-7.01 (m, 1H) 7.22-7.37 (m, 2H)7.42-7.55 (m, 1H) 7.64-7.72 (m, 1H) 7.75-7.88 (m, 1H); MS(ESI) m/z 361(M+H)⁺.

Example 67N²-acetyl-N¹-[3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-L-leucinamide

The product of Example 64A (39 mg, 0.14 mmol) and N-acetyl-L-leucine (29mg, 0.17 mmol) were processed using the method described in Example 3 toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.78-1.07 (m,6H) 1.43-1.57 (m, 1H) 1.57-1.75 (m, 2H) 1.81-1.92 (m, 3H) 3.22-3.26 (m,3H) 3.72 (t, 2H) 4.44-4.55 (m, 1H) 4.55-4.67 (m, 2H) 7.24-7.40 (m, 1H)7.43-7.54 (m, 1H) 7.62-7.73 (m, 1H) 7.79-7.92 (m, 1H) 7.95-8.07 (m, 1H);MS(ESI) m/z 364 (M+H)⁺.

Example 683-(2-chlorophenyl)-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]propanamide

The product of Example 64A (39 mg, 0.14 mmol) and3-(2-chlorophenyl)propionic acid (31 mg, 0.17 mmol) were processed usingthe method described in Example 3 to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.82 (t, 2H) 3.08 (t, 2H) 3.18-3.25 (m, 3H)3.79 (t, 2H) 4.54 (t, 2H) 7.17-7.29 (m, 2H) 7.30-7.44 (m, 3H) 7.45-7.54(m, 1H) 7.59-7.75 (m, 1H) 7.76-7.93 (m, 1H).

Example 69N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-3-methyl-2-phenylpentanamide

The product of Example 64A (39 mg, 0.14 mmol) and3-methyl-2-phenylvaleric acid (33 mg, 0.17 mmol) were processed usingthe method described in Example 3 to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 0.59-0.68 (m, 2H) 0.72-0.82 (m, 2H) 0.84-0.98(m, 3H) 1.08-1.27 (m, 1H) 2.21-2.39 (m, 1H) 3.11-3.24 (m, 3H) 3.38-3.50(m, 1H) 3.65-3.82 (m, 2H) 4.57 (t, 2H) 7.16-7.23 (m, 1H) 7.25-7.36 (m,3H) 7.37-7.54 (m, 3H) 7.60-7.73 (m, 1H) 7.75-7.88 (m, 1H); MS(ESI) m/z383 (M+H)⁺.

Example 704-ethyl-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and 4-ethylbenzoic acid(26 mg, 0.17 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.22 (t,3H) 2.66-2.72 (m, 2H) 3.25-3.26 (m, 3H) 3.85 (t, 2H) 4.75 (t, 2H)7.31-7.42 (m, 3H) 7.47-7.60 (m, 1H) 7.68-7.79 (m, 1H) 7.85-7.94 (m, 1H)8.12-8.23 (m, 2H); MS (ESI) m/z 341 (M+H)⁺.

Example 713-fluoro-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2-methylbenzamide

The product of Example 64A (39 mg, 0.14 mmol) and3-fluoro-2-methylbenzoic acid (26 mg, 0.17 mmol) were processed usingthe method described in Example 3 to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.51-2.53 (m, 3H) 3.22-3.25 (m, 3H) 3.80 (t,2H) 4.69 (t, 2H) 7.26-7.43 (m, 3H) 7.50-7.61 (m, 1H) 7.70-7.79 (m, 1H)7.86-7.99 (m, 2H); MS (ESI) m/z 345 (M+H)⁺.

Example 725-fluoro-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2-methylbenzamide

The product of Example 64A (39 mg, 0.14 mmol) and5-fluoro-2-methylbenzoic acid (26 mg, 0.17 mmol) were processed usingthe method described in Example 3 to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.51-2.53 (m, 3H) 3.22-3.25 (m, 3H) 3.80 (t,2H) 4.69 (t, 2H) 7.26-7.43 (m, 3H) 7.50-7.61 (m, 1H) 7.70-7.79 (m, 1H)7.86-7.99 (m, 2H); MS (ESI) m/z 345 (M+H)⁺.

Example 733-fluoro-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-4-methylbenzamide

The product of Example 64A (39 mg, 0.14 mmol) and5-fluoro-4-methylbenzoic acid (26 mg, 0.17 mmol) were processed usingthe method described in Example 3 to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.31-2.34 (m, 3H) 3.23-3.26 (m, 3H) 3.83 (t,2H) 4.77 (t, 2H) 7.33-7.40 (m, 1H) 7.41-7.49 (m, 1H) 7.49-7.59 (m, 1H)7.69-7.78 (m, 1H) 7.86-7.95 (m, 2H) 7.97-8.02 (m, 1H); MS (ESI) m/z 345(M+H)⁺.

Example 742,3-difluoro-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and 2,3-difluorobenzoicacid (27 mg, 0.17 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm3.20-3.26 (m, 3H) 3.82 (t, 2H) 4.72 (t, 2H) 7.28-7.36 (m, 1H) 7.37-7.43(m, 1H) 7.51-7.59 (m, 1H) 7.59-7.67 (m, 1H) 7.73-7.81 (m, 1H) 7.90-8.00(m, 2H); MS (ESI) m/z 349 (M+H)⁺.

Example 752,5-difluoro-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and 2,5-difluorobenzoicacid (27 mg, 0.17 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm3.23 (s, 3H) 3.82 (t, 2H) 4.72 (t, 2H) 7.38 (s, 2H) 7.46 (s, 1H) 7.54(s, 1H) 7.77 (s, 1H) 7.89 (s, 1H) 7.92-7.98 (m, 1H); MS (ESI) m/z 349(M+H)⁺.

Example 762-acetyl-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and 2-acetylbenzoic acid(28 mg, 0.17 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm2.44-2.48 (m, 3H) 3.21-3.25 (m, 3H) 3.77 (t, 2H) 4.67 (t, 2H) 7.30-7.44(m, 2H) 7.51-7.66 (m, 3H) 7.70-7.82 (m, 1H) 7.89-8.00 (m, 1H) 8.11-8.25(m, 1H); MS (ESI) m/z 355 (M+H)⁺.

Example 773-methoxy-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-4-methylbenzamide

The product of Example 64A (39 mg, 0.14 mmol) and3-methoxy-4-methylbenzoic acid (28 mg, 0.17 mmol) were processed usingthe method described in Example 3 to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.21-2.26 (m, 3H) 3.25-3.28 (m, 3H) 3.85 (t,2H) 3.88-3.90 (m, 3H) 4.76 (t, 2H) 7.26-7.31 (m, 1H) 7.32-7.39 (m, 1H)7.47-7.57 (m, 1H) 7.71-7.78 (m, 2H) 7.79-7.84 (m, 1H) 7.88-7.93 (m, 1H);MS (ESI) m/z 357 (M+H)⁺.

Example 782-ethoxy-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and 2-ethoxybenzoic acid(28 mg, 0.17 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm2.21-2.26 (m, 3H) 3.25-3.28 (m, 3H) 3.85 (t, 2H) 3.88-3.90 (m, 3H) 4.76(t, 2H) 7.26-7.31 (m, 1H) 7.32-7.39 (m, 1H) 7.47-7.57 (m, 1H) 7.71-7.78(m, 2H) 7.79-7.84 (m, 1H) 7.88-7.93 (m, 1H); MS (ESI) m/z 357 (M+H)⁺.

Example 79N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-4-(methylthio)benzamide

The product of Example 64A (39 mg, 0.14 mmol) and4-methylsulfanylbenzoic acid (29 mg, 0.17 mmol) were processed using themethod described in Example 3 to afford the title compound. ¹H NMR (500MHz, DMSO-d₆) δ ppm 2.53-2.58 (m, 3H) 3.22-3.27 (m, 3H) 3.84 (t, 2H)4.73 (t, 2H) 7.31-7.44 (m, 3H) 7.47-7.61 (m, 1H) 7.67-7.79 (m, 1H)7.82-8.02 (m, 1H) 8.08-8.22 (m, 2H); MS (ESI) m/z 359 (M+H)⁺.

Example 80N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-1-naphthamide

The product of Example 64A (39 mg, 0.14 mmol) and 1-naphthoic acid (29mg, 0.17 mmol) were processed using the method described in Example 3 toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.23-3.27 (m,3H) 3.90 (t, 2H) 4.71 (t, 2H) 7.32-7.42 (m, 1H) 7.45-7.68 (m, 4H)7.71-7.79 (m, 1H) 7.83-8.22 (m, 3H) 8.40-8.56 (m, 1H) 9.05-9.17 (m, 1H);MS (ESI) m/z 363 (M+H)⁺.

Example 81N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2-naphthamide

The product of Example 64A (39 mg, 0.14 mmol) and 2-naphthoic acid (29mg, 0.17 mmol) were processed using the method described in Example 3 toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.28-3.29 (m,3H) 3.91 (t, 2H) 4.78 (t, 2H) 7.25-7.44 (m, 1H) 7.50-7.58 (m, 1H)7.58-7.67 (m, 2H) 7.71-7.82 (m, 1H) 7.88-7.97 (m, 1H) 7.99-8.07 (m, 2H)8.08-8.21 (m, 1H) 8.26-8.40 (m, 1H) 8.72-8.93 (m, 1H); MS (ESI) m/z 363(M+H)⁺.

Example 825-chloro-2-hydroxy-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and5-chloro-2-hydroxybenzoic acid (29 mg, 0.17 mmol) were processed usingthe method described in Example 3 to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 3.22-3.25 (m, 3H) 3.85 (t, 2H) 4.73 (t, 2H)6.94-7.08 (m, 2H) 7.36-7.53 (m, 2H) 7.57-7.67 (m, 1H) 7.79-7.92 (m, 1H)7.96-8.09 (m, 2H); MS (ESI) m/z 363 (M+H)⁺.

Example 835-chloro-2-methoxy-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and5-chloro-2-methoxybenzoic acid (32 mg, 0.17 mmol) were processed usingthe method described in Example 3 to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 3.22-3.26 (m, 3H) 3.80 (t, 2H) 3.83-3.88 (m,3H) 4.62 (t, 2H) 7.13-7.23 (m, 1H) 7.32-7.43 (m, 1H) 7.46-7.59 (m, 2H)7.69-7.77 (m, 1H) 7.79-7.88 (m, 1H) 7.88-7.98 (m, 1H); MS (ESI) m/z 377(M+H)⁺.

Example 841-hydroxy-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2-naphthamide

The product of Example 64A (39 mg, 0.14 mmol) and 1-hydroxy-2-naphthoicacid (32 mg, 0.17 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm3.25-3.28 (m, 3H) 3.89 (t, 2H) 4.75 (t, 2H) 7.35-7.47 (m, 2H) 7.53-7.63(m, 2H) 7.63-7.70 (m, 1H) 7.79-7.93 (m, 2H) 7.96-8.06 (m, 1H) 8.04-8.19(m, 1H) 8.23-8.40 (m, 1H); MS (ESI) m/z 379 (M+H)⁺.

Example 854-fluoro-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-1-naphthamide

The product of Example 64A (39 mg, 0.14 mmol) and 4-fluoro-1-naphthoicacid (32 mg, 0.17 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm3.22-3.26 (m, 3H) 3.83 (t, 2H) 4.67 (t, 2H) 7.35-7.59 (m, 3H) 7.65-7.82(m, 3H) 7.83-8.03 (m, 1H) 8.09-8.28 (m, 1H) 8.46-8.71 (m, 1H) 9.08-9.38(m, 1H); MS (ESI) m/z 381 (M+H)⁺.

Example 862-methoxy-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-4-(methylthio)benzamide

The product of Example 64A (39 mg, 0.14 mmol) and2-methoxy-4-methylsulfanylbenzoic acid (34 mg, 0.17 mmol) were processedusing the method described in Example 3 to afford the title compound. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.53-2.61 (m, 3H) 3.21-3.25 (m, 3H) 3.79(t, 2H) 3.82-3.89 (m, 3H) 4.58 (t, 2H) 6.73-7.05 (m, 2H) 7.25-7.38 (m,1H) 7.47-7.61 (m, 1H) 7.60-7.78 (m, 1H) 7.80-7.91 (m, 1H) 7.89-8.09 (m,1H); MS (ESI) m/z 389 (M+H)⁺.

Example 872-chloro-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-5-(methylthio)benzamide

The product of Example 64A (39 mg, 0.14 mmol) and2-chloro-5-methylsulfanylbenzoic acid (34 mg, 0.17 mmol) were processedusing the method described in Example 3 to afford the title compound. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.52-2.56 (m, 3H) 3.20-3.26 (m, 3H) 3.82(t, 2H) 4.68 (t, 2H) 7.33-7.43 (m, 2H) 7.44-7.51 (m, 1H) 7.51-7.58 (m,1H) 7.71-7.86 (m, 2H) 7.91-8.00 (m, 1H); MS (ESI) m/z 393 (M+H)⁺.

Example 882-fluoro-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

The product of Example 64A (39 mg, 0.14 mmol) and2-fluoro-5-trifluoromethylbenzoic acid (34 mg, 0.17 mmol) were processedusing the method described in Example 3 to afford the title compound. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 3.23-3.26 (m, 3H) 3.84 (t, 2H) 4.67 (t, 2H)7.30-7.47 (m, 1H) 7.52-7.64 (m, 2H) 7.72-7.89 (m, 1H) 7.91-8.07 (m, 2H)8.34-8.58 (m, 1H); MS (ESI) m/z 399 (M+H)⁺.

Example 892-benzyl-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and α-phenyl-o-toluic acid(36 mg, 0.17 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm3.18-3.20 (m, 3H) 3.72 (t, 2H) 4.48-4.52 (m, 2H) 4.63 (t, 2H) 7.07-7.30(m, 6H) 7.30-7.41 (m, 2H) 7.40-7.47 (m, 1H) 7.49-7.57 (m, 1H) 7.67-7.79(m, 1H) 7.85-7.96 (m, 1H) 8.02-8.12 (m, 1H); MS (ESI) m/z 403 (M+H)⁺.

Example 902-chloro-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

The product of Example 64A (39 mg, 0.14 mmol) and2-chloro-5-trifluoromethylbenzoic acid (38 mg, 0.17 mmol) were processedusing the method described in Example 3 to afford the title compound. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 3.20-3.25 (s, 3H) 3.80 (t, 2H) 4.70 (t, 2H)7.35-7.45 (m, 1H) 7.50-7.65 (m, 1H) 7.76-7.83 (m, 2H) 7.84-7.91 (m, 1H)7.94-8.03 (m, 1H) 8.22-8.32 (m, 1H); MS (ESI) m/z 415 (M+H)⁺.

Example 91N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2-(2-phenylethyl)benzamide

The product of Example 64A (39 mg, 0.14 mmol) and 2-phenethylbenzoicacid (38 mg, 0.17 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm2.78-2.95 (m, 2H) 3.16-3.22 (m, 3H) 3.32-3.37 (m, 2H) 3.76 (t, 2H) 4.65(t, 2H) 6.99-7.46 (m, 9H) 7.49-7.57 (m, 1H) 7.67-7.80 (m, 1H) 7.82-7.97(m, 1H) 7.97-8.15 (m, 1H); MS (ESI) m/z 417 (M+H)⁺.

Example 922-bromo-5-methoxy-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and2-bromo-5-methoxybenzoic acid (39 mg, 0.17 mmol) were processed usingthe method described in Example 3 to afford the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 3.20-3.26 (m, 3H) 3.72-3.87 (m, 5H) 4.67 (t,2H) 6.91-7.08 (m, 1H) 7.30-7.43 (m, 1H) 7.45-7.51 (m, 1H) 7.51-7.65 (m,2H) 7.70-7.83 (m, 1H) 7.86-7.98 (m, 1H); MS (ESI) m/z 423 (M+H)⁺.

Example 932-iodo-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and 2-iodobenzoic acid (42mg, 0.17 mmol) were processed using the method described in Example 3 toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.20-3.24 (m,3H) 3.81 (t, 2H) 4.69 (t, 2H) 7.15-7.25 (m, 1H) 7.34-7.41 (m, 1H)7.47-7.62 (m, 2H) 7.70-7.81 (m, 1H) 7.87-7.97 (m, 2H) 7.97-8.03 (m, 1H);MS (ESI) m/z 439 (M+H)⁺.

Example 943-iodo-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and 3-iodobenzoic acid (42mg, 0.17 mmol) were processed using the method described in Example 3 toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.26-3.27 (m,3H) 3.79 (t, 2H) 4.76 (t, 2H) 7.26-7.43 (m, 2H) 7.48-7.61 (m, 1H)7.69-7.81 (m, 1H) 7.89-8.00 (m, 2H) 8.18-8.31 (m, 1H) 8.49-8.59 (m, 1H);MS (ESI) m/z 439 (M+H)⁺.

Example 954-iodo-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]benzamide

The product of Example 64A (39 mg, 0.14 mmol) and 4-iodobenzoic acid (42mg, 0.17 mmol) were processed using the method described in Example 3 toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.23-3.25 (m,3H) 3.80 (t, 2H) 4.75 (t, 2H) 7.29-7.45 (m, 1H) 7.47-7.62 (m, 1H)7.70-7.80 (m, 1H) 7.85-7.96 (m, 3H) 7.98-8.05 (m, 2H); MS (ESI) m/z 439(M+H)⁺.

Example 96N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-3-methylbutanamide

The product of Example 64A (39 mg, 0.14 mmol) and isovaleric acid (17mg, 0.17 mmol) were processed using the method described in Example 3 toafford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.93 (d, 6H)2.10-2.23 (m, 1H) 2.37 (d, 2H) 3.21-3.25 (m, 3H) 3.74 (t, 2H) 4.57 (t,2H) 7.31 (m, 1H) 7.48 (m, 1H) 7.66 (m, 1H) 7.83 (m, 1H); MS (ESI) m/z393 (M+H)⁺.

Example 97N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2-methylpentanamide

The product of Example 64A (39 mg, 0.14 mmol) and 2-methylvaleric acid(20 mg, 0.17 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.88 (t,3H) 1.14 (d, 3H) 1.21-1.34 (m, 2H) 1.35-1.47 (m, 1H) 1.63-1.76 (m, 1H)2.53-2.62 (m, 1H) 3.22-3.26 (m, 3H) 3.75 (t, 2H) 4.58 (t, 2H) 7.31 (m,1H) 7.49 (m, 1H) 7.66 (m, 1H) 7.83 (m, 1H); MS (ESI) m/z 307 (M+H)⁺.

Example 98N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-3-methylpentanamide

The product of Example 64A (39 mg, 0.14 mmol) and 3-methylvaleric acid(20 mg, 0.17 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.82-0.96 (m, 6H) 1.14-1.27 (m, 1H) 1.31-1.44 (m, 1H) 1.87-2.05 (m, 1H)2.25-2.34 (m, 1H) 2.43-2.49 (m, 1H) 3.21-3.26 (m, 3H) 3.74 (t, 2H) 4.56(t, 2H) 7.31 (m, 1H) 7.48 (m, 1H) 7.66 (m, 1H) 7.84 (m, 1H); MS (ESI)m/z 307 (M+H)⁺.

Example 99N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-4-methylpentanamide

The product of Example 64A (39 mg, 0.14 mmol) and 4-methylvaleric acid(20 mg, 0.17 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.90 (d,6H) 1.49-1.61 (m, 3H) 2.45-2.50 (m, 2H) 3.21-3.26 (m, 3H) 3.74 (t, 2H)4.58 (t, 2H) 7.32 (m, 1H) 7.48 (m, 1H) 7.66 (m, 1H) 7.84 (m, 1H); MS(ESI) m/z 307 (M+H)⁺.

Example 100N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2,2-dimethylbutanamide

The product of Example 64A (39 mg, 0.14 mmol) and 2,2-dimethylbutyricacid (20 mg, 0.17 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.76 (t, 3H) 1.11-1.23 (m, 6H) 1.62 (t, 2H) 3.18-3.27 (m, 3H) 3.75 (t,2H) 4.58 (t, 2H) 7.26 (m, 1H) 7.46 (m, 1H) 7.66 (m, 1H) 7.84 (m, 1H); MS(ESI) m/z 307 (M+H)⁺.

Example 101N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-3,3-dimethylbutanamide

The product of Example 64A (0.64 g, 2.2 mmol) and 3,3-dimethyl-butyricacid (0.26 mL, 2.0 mmol) were processed using the method described inExample 3. Purification by column chromatography (SiO₂, 20-30% ethylacetate/hexanes gradient) afforded 0.44 g (71%) of the title compound.¹H NMR (DMSO-d₆, 300 MHz) δ ppm 1.03 (s, 9H), 2.36-2.43 (s, 2H), 3.22(s, 3H), 3.73 (t, J=5.4 Hz, 2H), 4.56 (t, J=5.4 Hz, 2H), 7.32 (m, 1H),7.49 (td, J=7.8, 1.0 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.84 (dd, J=8.0,1.2 Hz, 1H); MS (DCI/NH₃) m/z 331 (M+H)⁺. Anal. Calculated forC₁₆H₂₂N₂O₂S: C, 62.71; H, 7.24; N, 9.14. Found: C, 62.79; H, 7.41; N,9.06.

Example 1022-ethyl-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]butanamide

The product of Example 64A (39 mg, 0.14 mmol) and 2-ethylbutyric acid(20 mg, 0.17 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.84 (t,6H) 1.47-1.59 (m, 2H) 1.60-1.72 (m, 2H) 2.27-2.39 (m, 1H) 3.21-3.26 (m,3H) 3.75 (t, 2H) 4.58 (t, 2H) 7.32 (m, 1H) 7.48 (m, 1H) 7.65 (m, 1H)7.82 (m, 1H); MS (ESI) m/z 307 (M+H)⁺.

Example 103N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]cyclopentanecarboxamide

The product of Example 64A (39 mg, 0.14 mmol) and cyclopentanecarboxylicacid (19 mg, 0.17 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.50-1.62 (m, 2H) 1.62-1.72 (m, 2H) 1.76-1.95 (m, 4H) 2.85-2.98 (m, 1H)3.22-3.26 (m, 3H) 3.74 (t, 2H) 4.56 (m, 2H) 7.31 (m, 1H) 7.48 (m, 1H)7.66 (m, 1H) 7.83 (d, 1H); MS (ESI) m/z 305 (M+H)⁺.

Example 1042-cyclopentyl-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]acetamide

The product of Example 64A (39 mg, 0.14 mmol) and cyclopentylacetic acid(22 mg, 0.17 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.09-1.25 (m, 2H) 1.44-1.56 (m, 2H) 1.55-1.65 (m, 2H) 1.70-1.84 (m, 2H)2.20-2.38 (m, 1H) 2.46-2.49 (m, 1H) 3.21-3.24 (m, 3H) 3.24-3.29 (m, 1H)3.74 (t, 2H) 4.56 (t, 2H) 7.32 (m, 1H) 7.49 (m, 1H) 7.65 (m, 1H) 7.83(m, 1H); MS (ESI) m/z 319 (M+H)⁺.

Example 105N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]cyclohexanecarboxamide

The product of Example 64A (39 mg, 0.14 mmol) and cyclohexanecarboxylicacid (22 mg, 0.17 mmol) were processed using the method described inExample 3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.13-1.36 (m, 3H) 1.37-1.52 (m, 2H) 1.58-1.67 (m, 1H) 1.66-1.80 (m, 2H)1.84-2.00 (m, 2H) 2.32-2.46 (m, 1H) 3.22-3.25 (m, 3H) 3.75 (t, 2H) 4.56(t, 2H) 7.30 (m, 1H) 7.48 (m, 1H) 7.65 (m, 1H) 7.83 (m, 1H); MS (ESI)m/z 319 (M+H)⁺.

Example 106N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-1-methylcyclohexanecarboxamide

The product of Example 64A (39 mg, 0.14 mmol) and1-methylcyclohexane-carboxylic acid (24 mg, 0.17 mmol) were processedusing the method described in Example 3 to afford the title compound. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.10-1.16 (m, 3H) 1.21-1.39 (m, 5H)1.40-1.48 (m, 1H) 1.48-1.58 (m, 2H) 2.06-2.21 (m, 2H) 3.21-3.25 (m, 3H)3.76 (t, 2H) 4.58 (t, 2H) 7.30 (m, 1H) 7.47 (m, 1H) 7.65 (m, 1H) 7.82(m, 1H); MS (ESI) m/z 333 (M+H)⁺.

Example 107cis-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2-methylcyclohexanecarboxamide

The product of Example 64A (39 mg, 0.14 mmol) and(cis)-2-methylcyclohexanecarboxylic acid (24 mg, 0.17 mmol) wereprocessed using the method described in Example 3 to afford the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.79 (d, 3H) 1.14-1.87 (m, 8H)2.24-2.39 (m, 1H) 2.56-2.65 (m, 1H) 3.19-3.23 (m, 3H) 3.72 (t, 2H) 4.54(t, 2H) 7.22-7.37 (m, 1H) 7.42-7.50 (m, 1H) 7.58-7.67 (m, 1H) 7.75-7.88(m, 1H); MS (ESI) m/z 333 (M+H)⁺.

Example 108N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-4-methylcyclohexanecarboxamide

The product of Example 64A (39 mg, 0.14 mmol) and4-methylcyclohexanecarboxylic acid (24 mg, 0.17 mmol) were processedusing the method described in Example 3 to afford the title compound. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 0.78-0.91 (m, 3H) 0.94-1.26 (m, 2H)1.38-1.63 (m, 4H) 1.69-2.01 (m, 1H) 2.04-2.40 (m, 2H) 2.53-2.65 (m, 1H)3.19-3.26 (m, 3H) 3.76 (t, 2H) 4.56 (t, 2H) 7.23-7.37 (m, 1H) 7.40-7.56(m, 1H) 7.59-7.70 (m, 1H) 7.76-7.86 (m, 1H); MS (ESI) m/z 333 (M+H)⁺.

Example 1092-cyclohexyl-N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]acetamide

The product of Example 64A (39 mg, 0.14 mmol) and cyclohexylacetic acid(24 mg, 0.17 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.86-1.05 (m, 2H) 1.06-1.35 (m, 3H) 1.54-1.75 (m, 5H) 1.77-1.92 (m, 1H)2.36 (d, 2H) 3.19-3.25 (m, 3H) 3.75 (t, 2H) 4.54 (t, 2H) 7.25-7.36 (m,1H) 7.43-7.56 (m, 1H) 7.60-7.69 (m, 1H) 7.77-7.88 (m, 1H); MS (ESI) m/z333 (M+H)⁺.

Example 110N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]cyclohepanecarboxamide

The product of Example 64A (39 mg, 0.14 mmol) and cycloheptylacetic acid(24 mg, 0.17 mmol) were processed using the method described in Example3 to afford the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.42-1.62 (m, 6H) 1.63-1.82 (m, 4H) 1.85-2.05 (m, 2H) 2.54-2.72 (m, 1H)3.18-3.26 (m, 3H) 3.72 (t, 2H) 4.55 (t, 2H) 7.23-7.40 (m, 1H) 7.42-7.55(m, 1H) 7.60-7.72 (m, 1H) 7.75-7.88 (m, 1H); MS (ESI) m/z 333 (M+H)⁺.

Example 111N-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-5-methylthiophene-2-carboxamide

The product of Example 64A (39 mg, 0.14 mmol) and5-methylthiophene-2-carboxylic acid (28 mg, 0.20 mmol) were processedusing the method described in Example 3 to afford the title compound. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.51 (s, 3H) 3.26 (s, 3H) 3.82 (t, 2H) 4.66(t, 2H) 6.91-6.93 (m, 1H) 7.35 (t, 1H) 7.51 (t, 1H) 7.68-7.72 (m, 2H)7.89 (d, 1H); MS (ESI) m/z 332 (M+H)⁺.

Example 112N-[(2Z)-6-fluoro-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 112AN-(6-fluoro-1,3-benzothiazol-2-yl)-2,2,3,3-tetramethylcyclopropanecarboxamide

A mixture of 6-fluoro-benzothiazol-2-ylamine (1 equiv),N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1 equiv),1-hydroxybenzotriazole, triethylamine (1.1 equiv), and2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.8 equiv) in 3:1THF/Et₃N (1 M) and were stirred overnight at room temperature. Themixture was diluted with EtOAc, washed with 1 M aqueous NaHCO₃, dried(Na₂SO₄), filtered, and concentrated. Puried by silica gelchromatography afforded the title compound. MS (ESI⁺) m/z 293 (M+H)⁺.

Example 112B 2,2,3,3-Tetramethylcyclopropanecarboxylic acid[6-fluoro-3-(2-methoxyethyl)-3H-benzothiazol-2-ylidene]-amide

To a solution of the product of Example 112A (1 equiv) in 1:1 DMF/THF(0.1 M) was added sodium hydride (60% dispersion in mineral oil, 1.2equiv) and 2-bromoethyl methyl ether (1.2 equiv).

The mixture was stirred at 65° C. overnight then cooled to ambienttemperature and diluted with EtOAc. The mixture was washed with 1 Msaturated aqueous NaHCO₃, dried (Na₂SO₄), filtered and concentrated.Purifed by silica gel chromatography afforded the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.20 (s, 6H), 1.27 (s, 6H), 1.60 (s, 1H), 3.23(s, 3H), 3.72 (t, J=5.4 Hz, 2H), 4.54 (t, J=5.4 Hz, 2H), 7.33 (td,J=9.0, 2.7 Hz, 1H), 7.65 (dd, J=8.8, 4.4 Hz, 1H), 7.75 (dd, J=8.1, 2.7Hz, 1H); MS (ESI⁺) m/z 351 (M+H)⁺.

Example 1132-cyclopentyl-N-[(2Z)-6-fluoro-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]acetamideExample 113A 6-Fluoro-3-(2-methoxyethyl)-3H-benzothiazol-2-ylideneaminehydrobromide

Commercially available 6-fluoro-benzothiazol-2-ylamine and 2-bromoethylmethyl ether were processed as described for example 12A to afford thetitle compound. MS (ESI⁺) m/z 227 (M+H)⁺.

Example 113B2-cyclopentyl-N-[(2Z)-6-fluoro-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]acetamide

The product from Example 113A and cyclopentylacetyl chloride wereprocessed as described for example 11 to afford the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 4.54 (d, J=5.76 Hz, 2H) 7.65 (t, J=8.14 Hz,1H) 7.75 (dd, J=8.81, 2.71 Hz, 1H) 7.83 (dd, J=7.97, 1.53 Hz, 2H) 7.97(dd, J=8.14, 1.36 Hz, 1H) 8.41 (d, J=3.05 Hz, 1H); MS (ESI⁺) m/z 337(M+H)⁺; Anal. Calculated for C₁₇H₂₁FN₂O₂S: C, 60.69; H, 6.29; N, 8.33.Found: C, 60.67; H, 6.41; N, 8.25.

Example 114N-[(2Z)-6-fluoro-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2-tetrahydro-2H-pyran-4-ylacetamideExample 114A (Tetrahydro-pyran-4-yl)-acetyl chloride

Commercially available (tetrahydro-pyran-4-yl)-acetic acid and oxalylchloride were processed as described for example 9A to afford the titlecompound. MS (DCI/NH₃) m/z 159 (M+H)⁺.

Example 114BN-[6-Fluoro-3-(2-methoxyethyl)-3H-benzothiazol-2-ylidene]-2-(tetrahydro-pyran-4-yl)-acetamide

The product from Example 113A and the product from Example 114A wereprocessed as described for Example 11 to afford the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.13-1.35 (m, 2H), 1.52-1.66 (m, 2H), 2.05(d, 1H), 2.43 (d, J=7.1 Hz, 2H), 3.22 (s, 3H), 3.72 (t, J=5.3 Hz, 2H),3.78-3.88 (m, 4H), 4.56 (t, J=5.3 Hz, 2H), 7.36 (td, J=9.0, 2.7 Hz, 1H),7.70 (dd, J=9.0, 4.2 Hz, 1H), 7.81 (dd, J=8.5, 2.7 Hz, 1H); MS (ESI⁺)m/z 353 (M+H)⁺; Anal. Calculated for C₁₇H₂₁FN₂O₃S: C, 57.94; H, 6.01; N,7.95. Found: C, 58.03; H, 5.97; N, 7.87.

Example 1155-fluoro-N-[(2Z)-6-fluoro-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2-methoxybenzamide

The product from Example 113A and 5-fluoro-2-methoxy-benzoic acid wereprocessed using the methods described in Example 13 to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.23 (s, 3H), 3.72-3.87 (m,5H), 4.65 (t, J=5.4 Hz, 2H), 7.15 (dd, J=9.3, 4.2 Hz, 1H), 7.37 (dd,2H), 7.64 (dd, J=9.2, 3.4 Hz, 1H), 7.77 (dd, J=9.2, 4.4 Hz, 1H), 7.88(dd, J=8.1, 2.7 Hz, 1H); MS (ESI⁺) m/z 379 (M+H)⁺; Anal. Calculated forC₁₈H₁₆F₂N₂O₃S: C, 57.13; H, 4.26; N, 7.40. Found: C, 57.05; H, 4.08; N,7.35.

Example 1165-chloro-N-[(2Z)-6-fluoro-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]-2-methoxybenzamide

The product from Example 113A and 5-chloro-2-methoxybenzoic acid wereprocessed using the methods described in Example 13 to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.24 (s, 3H), 3.79 (t, J=5.3Hz, 2H), 3.83 (s, 3H), 4.65 (t, J=5.3 Hz, 2H), 7.17 (d, J=9.2 Hz, 1H),7.41 (td, J=9.1, 2.5 Hz, 1H), 7.52 (dd, J=8.8, 2.7 Hz, 1H), 7.78 (dd,J=9.0, 4.2 Hz, 1H), 7.83 (d, J=2.7 Hz, 1H), 7.89 (dd, J=8.5, 2.7 Hz,1H); MS (ESI⁺) m/z 395 (M+H)⁺; Anal. Calculated for C₁₈H₁₆ClFN₂O₃S: C,54.75; H, 4.08; N, 7.09. Found: C, 54.29; H, 3.94; N, 6.99.

Example 117N-[(2Z)-3-(2-methoxyethyl)-4-methyl-5-morpholin-4-yl-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 117A 2,2,3,3-Tetramethylcyclopropanecarboxylic acid(4-methyl-5-morpholin-4-yl-thiazol-2-yl)-amide

A mixture of 4-methyl-5-morpholin-4-yl-thiazol-2-ylamine (prepared usingthe method described in Christopher et al., Bioorganic and MedicinalChemistry Letters 2004, 14(22), 5521-5525),N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride,1-hydroxybenzotriazole, triethylamine, and2,2,3,3-tetramethylcyclopropanecarboxylic acid were processed using themethod described in Example 58 to afford the title compound. MS (ESI)m/z 324 (M+H)⁺.

Example 117B 2,2,3,3-Tetramethylcyclopropanecarboxylic acid[3-(2-methoxyethyl)-4-methyl-5-morpholin-4-yl-3H-thiazol-2-ylidene]-amide

The product from Example 117A was processed using the method describedin Example 112B to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 1.16 (s, 6H), 1.23 (s, 6H), 1.44 (s, 1H), 2.22 (s, 3H), 2.70-2.79(m, 4H), 3.24 (s, 3H), 3.62 (t, J=5.3 Hz, 2H), 3.66-3.72 (m, 4H), 4.21(t, J=5.4 Hz, 2H); MS (ESI) m/z 382 (M+H)⁺.

Example 118N-[(2Z)-5-chloro-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 118A 2,2,3,3-Tetramethylcyclopropanecarboxylic acid(5-chloro-4-methyl-thiazol-2-yl)-amide

A mixture of 2-amino-5-chloro-2-methyl-thiazole (Matsuo, Masaaki; Ogino,Takashi; Igari, Norihiro; Seno, Hachiro; Shimomura, Kyoichi., EP 412404)(150 mg, 0.81 mmol), 2,2,3,3-tetramethylcyclopropanecarbonyl chloride(143 mg, 0.89 mmol), 4-dimethylaminopyridine (50.0 mg, 0.41 mmol) andtriethylamine (226 μL, 1.62 mmol) in 15 mL of THF heated at reflux for48 hours. The mixture was cooled to ambient temperature, diluted withEtOAc and washed with brine. The layers were separated and the aqueousphase was extracted with EtOAc (2×). The combined organic extracts weredried (Na₂SO₄), filtered, and concentrated. Purification by silica gelchromatography afforded the title compound: MS (LC/MS) m/z 273 (M+H)⁺.

Example 118B 2,2,3,3-Tetramethylcyclopropanecarboxylic acid(5-chloro-3-(2-methoxy-ethy)-4-methyl-3H-thiazol-2-ylidene]-amide

A mixture of the product of Example 118A (150 mg, 0.55 mmol), NaH (60%dispersion in mineral oil, 29.0 mg, 0.71 mmol) and 2-bromoethyl methylether (57 μl, 0.61 mmol) in 20 mL of 2:1 THF/DMF was processed accordingto the method desribed in Example 112B to provide the title compound: ¹HNMR (300 MHz, DMSO-d₆) δ 1.18 (s, 6H) 1.23 (s, 6H) 1.50 (s, 1H) 2.29 (s,3H) 3.25 (s, 3H) 3.63 (t, J=5.3 Hz, 2H) 4.27 (t, J=5.3 Hz, 2H); MS(DCI/NH₃) m/z 331 (M+H)⁺.

Example 119 N-[(2Z)-3-(2-methoxyethyl)-5-methyl-4-phenyl-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide Example 119A3-(2-methoxyethyl)-5-methyl-4-phenyl-3H-thiazol-2-ylideneaminehydrobromide

A mixture of 5-methyl-4-phenyl-thiazol-2-ylamine (300 mg, 1.58 mmol) and2-bromoethyl methyl ether (300 μl, 3.20 mmol) was processed using themethod described in Example 12A to provide the title compound.

Example 119B 2,2,3,3-Tetramethylcyclopropanecarboxylic acid[3-(2-methoxy-ethy)-5-methyl-4-phenyl-3H-thiazol-2-ylidene]-amide

A mixture of the product of Example 119A (290 mg, 1.16 mmol),2,2,3,3-tetramethylcyclopropanecarboxylic acid (182 mg, 1.28 mmol), HATU(661 mg, 1.74 mmol) and triethylamine (0.97 mL, 6.96 mmol) in 15 mL ofDMF was processed according to the method of Example 2B to provide thetitle compound: ¹H NMR (400 MHz, DMSO-d₆) δ 1.17 (s, 6H) 1.26 (s, 6H)1.49 (s, 1H) 2.01 (s, 3H) 3.02 (s, 3H) 3.43 (t, J=6.0 Hz, 2H) 4.06 (t,J=5.8 Hz, 2H) 7.39-7.43 (m, 2H) 7.50-7.57 (m, 3H); MS (DCI/NH₃) m/z 373(M+H)⁺.

Example 120N-[(2Z)-4-(4-chlorophenyl)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 120A4-(4-chlorophenyl)-3-(2-methoxyethyl)-5-methyl-3H-thiazol-2-ylideneaminehydrobromide

A mixture of 4-(4-chlorophenyl)-5-methyl-thiazol-2-ylamine (420 mg, 1.87mmol) and 2-bromoethyl methyl ether (600 μL, 6.40 mmol) was processedaccording to the method of Example 12A to provide the title compound: MS(DCI/NH₃) m/z 283 (M+H)⁺.

Example 120B 2,2,3,3-Tetramethylcyclopropanecarboxylic acid[4-(4-chlorophenyl)-3-(2-methoxy-ethy)-5-methyl-3H-thiazol-2-ylidene]-amide

A mixture of the product of Example 120A (156 mg, 0.55 mmol),2,2,3,3-tetramethylcyclopropanecarboxylic acid (94 mg, 0.66 mmol), HATU(479 mg, 0.83 mmol) and triethylamine (0.46 mL, 3.30 mmol) in 10 mL ofDMF was processed according to the method of Example 2B to provide thetitle compound: ¹H NMR (500 MHz, DMSO-d₆) δ 1.17 (s, 6H) 1.25 (s, 6H)1.49 (s, 1H) 2.00 (s, 3H) 3.04 (s, 3H) 3.44 (t, J=5.8 Hz, 2H) 4.04 (t,J=5.8 Hz, 2H) 7.45 (d, J=8.2 Hz, 2H) 7.60 (d, J=8.5 Hz, 2H); MS(DCI/NH₃) m/z 407 (M+H)⁺.

Example 121N-[(2Z)-3-(2-methoxyethyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 121A3-(2-methoxy-ethy)-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylideneaminehydrobromide

A mixture of 4,5,6,7-tetrahydro-benzothiazol-2-ylamine (300 mg, 1.94mmol) and 2-bromoethyl methyl ether (600 μL, 6.40 mmol) was processedaccording to the method of Example 12A to provide the title compound ascrude product: MS (LC/MS) m/z 213 (M+H)⁺.

Example 121B 2,2,3,3-Tetramethylcyclopropanecarboxylic acid[3-(2-methoxy-ethy)-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene]-amide

A mixture of the product of Example 121A (156 mg, 0.55 mmol),2,2,3,3-tetramethylcyclopropanecarboxylic acid (94 mg, 0.66 mmol), HATU(479 mg, 0.83 mmol) and triethylamine (0.46 mL, 3.30 mmol) in 10 mL ofDMF was processed according to the method of Example 2B to provide thetitle compound: ¹H NMR (500 MHz, DMSO-d₆) δ 1.16 (s, 6H) 1.23 (s, 6H)1.45 (s, 1H) 1.69-1.82 (m, 4H) 2.43-2.48 (m, 2H) 2.54-2.59 (m, 2H) 3.24(s, 3H) 3.60 (t, J=5.3 Hz, 2H) 4.16 (t, J=5.3 Hz, 2H); MS (DCI/NH₃) m/z337 (M+H)⁺.

Example 122N-[(2Z)-3-(2-methoxyethyl)-3,4,5,6-tetrahydro-2H-cyclopenta[d][1,3]thiazol-2-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 122A 2,2,3,3-Tetramethylcyclopropanecarboxylic acid(5,6-dihydro-4H-cyclopentathiazol-2-yl)-amide

A mixture of 5,6-dihydro-4H-cyclopentathiazole-2-ylamine (177 mg, 1.26mmol), 2,2,3,3-tetramethylcyclopropanecarboxylic acid (244 mg, 1.52mmol), 4-dimethylaminopyridine (50.0 mg, 0.41 mmol) and triethylamine(351 μL, 2.52 mmol) in 20 mL of THF was processed according to themethod of Example 118A to provide the title compound: MS (DCI/NH₃) m/z265 (M+H)⁺.

Example 122B 2,2,3,3-Tetramethylcyclopropanecarboxylic acid[3-(2-methoxy-ethy)-(3,4,5,6-tetrahydro-cyclopentathiazol-2-ylidene)-amide

A mixture of the product of Example 122A (254 mg, 0.95 mmol), NaH (60%dispersion in mineral oil, 50.0 mg, 1.22 mmol) and 2-bromoethyl methylether (100 μL, 1.07 mmol) in 30 mL of THF/DMF (2/1) was processedaccording to the method of Example 112B to provide the title compound:¹H NMR (500 MHz, DMSO-d₆) δ1.16 (s, 6H) 1.23 (s, 6H) 1.45 (s, 1H)2.31-2.38 (m, 2H) 2.72 (t, J=7.0 Hz, 2H) 2.78 (t, J=7.2 Hz, 2H) 3.24 (s,3H) 3.61 (t, J=5.3 Hz, 2H) 4.15 (t, J=5.2 Hz, 2H); MS (DCI/NH₃) m/z 323(M+H)⁺.

Example 123N-[(7Z)-8-(2-methoxyethyl)-5,8-dihydro[1,3]thiazolo[4,5-e][2,1,3]benzoxadiazol-7(4H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamideExample 123A 4,5-dihydro[1,3]thiazolo[4,5-e][2,1,3]benzoxadiazol-7-aminehydrobromide

To a solution of commercially available5-bromo-6,7-dihydro-5H-benzo[1,2,5]oxadiazol-4-one (1.1 g, 5.1 mmol) inabsolute ethanol (60 mL) was added thiourea. The reaction mixture wasstirred at 60° C. for overnight and then concentrated. The residue wastriturated in hexanes to afford 1.3 g (90%) of the title compound. MS(ESI⁺) m/z 195 (M+H)⁺.

Example 123BN-4,5-dihydro[1,3]thiazolo[4,5-e][2,1,3]benzoxadiazol-7-yl-2,2,3,3-tetramethylcyclopropanecarboxamide

Example 123A and 2,2,3,3-tetramethylcyclopropanecarbonyl chloride wereprocessed as described for example 118A to afford the title compound. MS(ESI⁺) m/z 319 (M+H)⁺.

Example 123CN-[(7Z)-8-(2-methoxyethyl)-5,8-dihydro[1,3]thiazolo[4,5-e][2,1,3]benzoxadiazol-7(4H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide

The product of Example 123B (1 equiv), potassium tert-butoxide (1.1equiv) and 2-bromoethyl methyl ether (1 equiv) were combined in DMF (0.1M) and heated in a SmithSynthesizer™ microwave at 250° C. for 15minutes. The mixture was diluted with EtOAc and washed with 1 M aqueousNaHCO₃. The phases were separated and the aqueous phase was extractedwith EtOAc (3×). The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated. Purification by silica gel chromatographyafforded the title compound and the product of Example 124. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.20 (s, 6H), 1.26 (s, 6H), 1.57 (s, 1H), 3.10 (t,J=7.5 Hz, 2H), 3.23 (s, 3H), 3.26 (t, J=7.4 Hz, 2H), 3.71 (t, J=5.8 Hz,2H), 4.67 (t, J=5.8 Hz, 2H); MS (ESI⁺) m/z 377 (M+H)⁺.

Example 124N-[(7Z)-8-(2-methoxyethyl)[1,3]thiazolo[4,5-e][2,1,3]benzoxadiazol-7(8H)-ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide

The title compound was obtained as byproduct during the synthesis ofexample 123C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23 (s, 6H), 1.29 (s,6H), 1.67 (s, 1H), 3.24 (s, 3H), 3.85 (t, J=5.7 Hz, 2H), 4.96 (t, J=5.5Hz, 2H), 7.94 (d, J=9.2 Hz, 1H), 8.06 (d, J=9.5 Hz, 1H); MS (ESI⁺) m/z374 (M+H)⁺.

Example 1252-Ethoxy-N-[(2Z)-3-(2-methoxyethyl)-4,6-dihydrofuro[3,4-d]thiazol-2(3H)-ylidene]-benzamideExample 125A 4-Bromo-dihydrofuran-3-one

The title compound was prepared according to the procedure using themethod described in Baker, Tracy J, Wiemer, David F, J. Org. Chem.,1998, 63(8), 2613-2618 and was used immediately using the methoddescribed in Example 125B.

Example 125B 3a-Ethoxy-3a,4,6,6a-tetrahydrofuro[3,4-d]thiazol-2-ylamine

The product of Example 125A and thiourea were processed using the methoddescribed in Example 123A to afford the title compound. MS (ESI⁺) m/z189 (M+H)⁺.

Example 125C3a-Ethoxy-3-(2-methoxy-ethyl)-tetrahydro-furo[3,4-d]thiazol-2-ylideneamine

The product from Example 125B and 1-bromo-2-methoxyethane were processedusing the method described in Example 12A to afford the title compound.MS (ESI⁺) m/z 247 (M+H)⁺.

Example 125D2-Ethoxy-N-[3a-ethoxy-3-(2-methoxy-ethyl)-tetrahydro-furo[3,4-d]thiazol-2-ylidene]-benzamide

The product from Example 125B and 2-ethoxybenzoyl chloride wereprocessed as described for example 118A to afford the title compound. MS(ESI⁺) m/z 395 (M+H)⁺.

Example 125E2-Ethoxy-N-[3-(2-methoxyethyl)-4,6-dihydro-3H-furo[3,4-d]thiazol-2-ylidene]-benzamide

To a solution of the product from Example 125D (15 mg, 0.04 mmol) intoluene (10 mL) was added p-toluenesulfonic acid monohydrate (2 mg). Themixture was refluxed for 3 hours and then cooled to room temperature,diluted with ethyl acetate, washed with 1M NaHCO₃, dried (Na₂SO₄),filtered and concentrated. Purification by preparative HPLC on a watersSymmetry C8 column (40 mm×100 mm, 7 μm particle size) using a gradientof 10% to 100% acetonitrile: ammonium acetate (10 mM) over 15 min at aflow rate of 70 mL/min afforded the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.33 (t, J=7.0 Hz, 3H), 3.24 (s, 3H), 3.65 (t, J=4.9 Hz,2H), 4.07 (q, J=6.8 Hz, 2H), 4.25 (t, J=5.1 Hz, 2H), 4.96 (s, 4H),6.92-7.01 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 7.36-7.44 (m, 1H), 7.74 (dd,J=7.5, 1.7 Hz, 1H); MS (ESI⁺) m/z 349 (M+H)⁺.

Example 1263-chloro-2-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-6-(trifluoromethyl)benzamideExample 126A 3-(2-Methoxy-ethyl)-4,5-dimethyl-3H-thiazol-2-ylideneamine

The product of Example 12A was purified via flash column chromatography(SiO₂, 9:1:0.1 CH₂Cl₂:CH₃OH:NH₄OH) to provide the title compuond. ¹H NMR(300 MHz, CDCl₃) δ ppm 2.18 (s, 6H) 3.32 (s, 3H) 3.78 (t, J=5.10 Hz, 2H)4.39 (t, J=4.70 Hz, 2H) 9.45 (s, 2H); MS (DCI/NH₃) m/z 187 (M+H)⁺.

Example 126B3-Chloro-2-fluoro-N-[3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-2-ylidene]-6-trifluoromethylbenzamide

To a suspension of the product of Example 126A (0.20 g, 1.1 mmol) in 35mL THF was added Et₃N (0.37 mL, 2.7 mmol). This mixture was cooled to 0°C. and 3-chloro-2-fluoro-6-trifluoromethyl benzoyl chloride (Alfa Aesar,0.35 g, 13 mmol) in 5 mL THF was added dropwise via syringe. The mixturewas allowed to stir at ambient temperature for 1 hour, then was warmedto reflux and was allowed to stir for 8 hours. The mixture was thencooled to ambient temperature and filtered. The filtrate wasconcentrated under reduced pressure and purified via flash columnchromatography (SiO₂, 7:3 hexanes:EtOAc) to provide the title compound(0.20 g, 0.50 mmol, 46% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 2.27 (s,3H), 2.28 (s, 3H), 3.27 (s, 3H), 3.68 (t, J=4.7 Hz, 2H), 4.28-4.37 (m,2H), 7.37-7.43 (m, 1H), 7.44-7.52 (m, 1H); MS (DCI/NH₃) m/z 411 (M+H)⁺;Anal. calculated for C₁₆H₁₅ClF₄N₂O₂S: C, 46.78; H, 3.68; N, 6.82. Found:C, 46.83; H, 3.30; N, 6.65.

Example 1275-chloro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-(trifluoromethyl)benzamide

To the product of Example 126A (0.20 g, 1.1 mmol) in 35 mL THF at 0° C.was added Et₃N (0.37 mL, 2.7 mmol) followed by5-chloro-2-trifluoromethyl-benzoyl chloride (Matrix, 0.26 g, 1.3 mmol)in 5 mL THF dropwise via syringe. This mixture was stirred at ambienttemperature for 1 hour then was warmed to reflux and allowed to stir for8 hours. The mixture was then cooled to ambient temperature andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified via flash column chromatography (SiO₂, 4:1hexanes:EtOAc) to provide the title compound (0.23 g, 0.57 mmol, 53%yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.30(s, 3H), 3.71 (t, J=4.9 Hz, 2H), 4.36 (t, J=4.9 Hz, 2H), 7.45 (ddd,J=8.5, 2.0, 0.7 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H);MS (DCI/NH₃) m/z 393 (M+H)⁺; Anal. calculated for C₁₆H₁₆ClF₃N₂O₂S: C,48.92; H, 4.11; N, 7.13. Found: C, 48.66; H, 3.81; N, 7.01.

Example 1282,3-dichloro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

To the product of Example 126A (0.20 g, 1.1 mmol) in 35 mL THF was addedEt₃N (0.37 mL, 2.7 mmol). This mixture was cooled to 0° C. and2,3-dichlorobenzoyl chloride (Lancaster, 0.27 g, 1.3 mmol) in 5 mL THFwas added dropwise via syringe. This mixture stirred at ambienttemperature for 1 hour then was warmed to reflux and was allowed to stirfor 3 hours. The mixture was cooled to ambient temperature and wasquenched with 5 mL saturated, aqueous NH₄Cl and diluted with 10 mLEtOAc. The layers were separated and the aqueous layer was extracted 2×5mL EtOAc and 2×5 mL CH₂Cl₂. The combined organics were washed 1×5 mLsaturated, aqueous NaCl then were dried over anhydrous Na₂SO₄, filtered,concentrated under reduced pressure and purified via flash columnchromatography (SiO₂, 10% CH₃OH:EtOAc). The material was still impure soit was purified again via flash column chromatography (SiO₂, 1:1hexanes:EtOAc) to provide the title compound (0.105 g, 0.29 mmol, 27%yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.30(s, 3H), 3.76 (t, J=4.6 Hz, 2H), 4.40 (t, J=4.2 Hz, 2H), 7.23 (t, J=7.7Hz, 1H), 7.49 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (dd, J=7.6, 1.5 Hz, 1H); MS(DCI/NH₃) m/z 359 (M+H)⁺; Anal. calculated for C₁₅H₁₆Cl₂N₂O₂S: C, 50.15;H, 4.49; N, 7.80. Found: C, 50.17; H, 4.26; N, 7.69.

Example 129N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxamide

To a solution of the product of Example 126A (0.20 g, 1.1 mmol) and Et₃N(0.45 mL, 3.2 mmol) in 30 mL THF was added2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonyl chloride (Acros, 0.34g, 1.6 mmol). This mixture was warmed to reflux and allowed to stir for2 hours. The mixture was then cooled to ambient temperature andconcentrated under reduced pressure. The residue was diluted with 10 mLEtOAc and washed with 5 mL saturated, aqueous NH₄Cl. The layers wereseparated and the aqueous layer was extracted 2×5 mL EtOAc. The combinedorganics were dried over anhydrous Na₂SO₄, filtered, concentrated underreduced pressure and purified via flash column chromatography (SiO₂, 4:1hexanes:EtOAc) to provide the title compound (0.21 mmol, 0.57 mmol, 53%yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.55 (s, 6H), 2.22 (s, 3H), 2.27(s, 3H), 3.02 (s, 2H), 3.31 (s, 3H), 3.77-3.89 (m, 2H), 4.33-4.50 (m,2H), 6.85 (t, J=7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 8.00 (d, J=8.1 Hz,1H); MS (DCI/NH₃) m/z 361 (M+H); Anal. calculated for C₁₉H₂₄N₂O₃S: C,63.31; H, 6.71; N, 7.77. Found: C, 63.19; H, 6.50; N, 7.66.

Example 1302,2-difluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-1,3-benzodioxole-4-carboxamide

To the product of Example 126A (0.20 g, 1.1 mmol) in 30 mL THF was addedEt₃N (0.37 mL, 2.7 mmol) followed by2,2-difluoro-1,3-benzodioxole-4-carbonyl chloride (Lancaster, 0.29 g,1.3 mmol). This mixture was stirred at ambient temperature for 17 hoursthen was warmed to reflux and allowed to stir for an additional 4 hours.The mixture was then cooled to ambient temperature and additional2,2-difluoro-1,3-benzodioxole-4-carbonyl chloride (73 mg, 0.33 mmol) andEt₃N (0.37 mL, 2.7 mmol) were added. This mixture was warmed to refluxat which temperature it stirred for 2 hours. The mixture was then cooledto ambient temperature, diluted with 10 mL EtOAc and washed with 5 mLsaturated, aqueous NH₄Cl. The layers were separated and the aqueouslayer was extracted 2×5 mL EtOAc. The combined organics were dried overanhydrous Na₂SO₄, filtered, concentrated under reduced pressure andpurified via flash column chromatography (SiO₂, 50% hexanes:EtOAc) toafford the title compound (0.22 g, 0.59 mmol, 55% yield). ¹H NMR (300MHz, CDCl₃) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.32 (s, 3H), 3.83 (t,J=5.1 Hz, 2H), 4.44 (t, J=5.1 Hz, 2H), 7.12 (d, J=4.4 Hz, 1H), 7.14 (s,1H), 7.89 (dd, J=6.6, 2.9 Hz, 1H); MS (DCI/NH₃) m/z 371 (M+H)⁺; Anal.calculated for C₁₆H₁₆F₂N₂O₄S: C, 51.89; H, 4.35; N, 7.56. Found: C,52.27; H, 4.24; N, 7.53.

Example 1315-bromo-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2,3-dihydro-1-benzofuran-7-carboxamide

The product of Example 126A (0.20 g, 1.1 mmol), Et₃N (0.45 mL, 3.2 mmol)and 5-bromo-2,3-dihydrobenzo[b]-furan-7-carbonyl chloride (Maybridge,0.42 g, 1.6 mmol) in 35 mL THF were processed as in Example 126B. Theresulting crude material was purified via flash column chromatography(SiO₂, 7:3 hexanes:EtOAc) to afford the title compound (0.16 g, 0.39mmol, 36% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 2.24 (s, 3H), 2.28 (s,3H), 3.23 (t, J=8.5 Hz, 2H), 3.33 (s, 3H), 3.78-3.87 (m, 2H), 4.45-4.56(m, 2H), 4.70-4.81 (m, 2H), 7.35-7.39 (m, 1H), 8.09 (d, J=2.0 Hz, 1H);MS (DCI/NH₃) m/z 411, 413 (M+H)⁺; Anal. calculated forC₁₇H₁₉BrN₂O₃S.0.3H₂O: C, 49.00; H, 4.74; N, 6.72. Found: C, 48.91; H,4.36; N, 6.57.

Example 1322-bromo-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of the product of Example 126A (0.20 g, 1.1 mmol) and Et₃N(0.3 mL, 2.2 mmol) in 25 mL THF was added 2-bromobenzoyl chloride(Aldrich, 0.18 mL, 1.4 mmol). This mixture stirred at ambienttemperature for 20 hours then was concentrated under reduced pressureand the residue was diluted with 10 mL EtOAc and washed with 5 mL NH₄Cl.The layers were separated and the aqueous layer was extracted (2×5 mLEtOAc). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, concentrated under reduced pressure and purified viarecrystallization with 50% hexanes/EtOAc to afford 0.18 g of the titlecompound (0.49 mmol, 46% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 2.26 (s,3H), 2.28 (s, 3H), 3.30 (s, 3H), 3.78 (t, J=5.1 Hz, 2H), 4.42 (t, J=5.1Hz, 2H), 7.22 (dt, J=7.8, 1.7 Hz, 1H), 7.34 (dt, J=7.5, 1.4 Hz, 1H),7.63 (dd, J=8.0, 1.2 Hz, 1H), 7.90 (dd, J=7.6, 1.9 Hz, 1H); MS (DCI/NH₃)m/z 369, 371 (M+H)⁺; Anal. calculated for C₁₅H₁₇BrN₂O₂S: C, 48.79; H,4.64; N, 7.59. Found: C, 48.84; H, 4.49; N, 7.40.

Example 1332,6-dichloro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 126A (0.20 g, 1.1 mmol), Et₃N (0.3 mL, 2.2 mmol)and 2,6-dichlorobenzoyl chloride (Aldrich, 0.2 mL, 1.4 mmol) in 25 mLTHF were processed as in Example 132 to afford the title compound (0.12g, 0.32 mmol, 30% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 2.28 (s, 6H),3.27 (s, 3H), 3.74 (t, J=4.6 Hz, 2H), 4.34-4.44 (m, 2H), 7.19 (dd,J=8.8, 6.8 Hz, 1H), 7.28-7.34 (m, 2H); MS (DCI/NH₃) m/z 359 (M+H)⁺.

Example 134N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]quinoline-4-carboxamideExample 134A Quinoline-4-carbonyl chloride

A solution of 4-quinolinecarboxylic acid (Aldrich, 0.25 g, 1.4 mmol) in5 mL of thionyl chloride was warmed to reflux and allowed to stir for 1hour. The mixture was then cooled to ambient temperature andconcentrated under reduced pressure. This material was dissolved in 10mL toluene and concentrated under reduced pressure (3×) to afford thetitle compound.

Example 134BN-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]quinoline-4-carboxamide

To a suspension of the product of Example 126A (0.20 g, 1.1 mmol) in 25mL THF was added Et₃N (0.3 mL, 2.2 mmol) followed by the freshlyprepared quinoline-4-carbonyl chloride. This mixture was warmed toreflux and allowed to stir for 18 hours. The material was thenconcentrated under reduced pressure and 10 mL EtOAc, 5 mL H₂O and 5 mLNH₄OH were added. The layers were separated and the aqueous layer wasextracted 2×5 mL EtOAc. The combined organic layers were dried overanhydrous Na₂SO₄, filtered, concentrated under reduced pressure andpurified via flash column chromatography (SiO₂, 5% CH₃OH in EtOAc) toafford the title compound (0.12 g, 0.35 mmol, 33% yield). ¹H NMR (300MHz, CD₃OD) δ ppm 2.32 (d, J=0.7 Hz, 3H), 2.35 (d, J=0.7 Hz, 3H), 3.31(s, 3H), 3.78 (t, J=5.3 Hz, 2H), 4.48 (t, J=5.1 Hz, 2H), 7.65 (ddd,J=8.5, 7.0, 1.2 Hz, 1H), 7.80 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 8.00 (d,J=4.4 Hz, 1H), 8.06-8.11 (m, 1H), 8.84 (ddd, J=8.5, 1.4, 0.7 Hz, 1H),8.93 (d, J=4.4 Hz, 1H); MS (DCI/NH₃) m/z 342 (M+H)⁺; Anal. calculatedfor C₁₈H₁₉N₃O₂S: C, 63.32; H, 5.61; N, 12.31. Found: C, 63.23; H, 5.46;N, 12.10.

Example 135N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]quinoline-5-carboxamide

The quinoline-5-carboxylic acid (Lancaster, 0.25 g, 1.4 mmol) wasconverted to quinoline-5-carbonyl chloride using 5 mL SOCl₂ using themethod described in Example 134A. The product of Example 126A (0.20 g,1.1 mmol), Et₃N (0.3 mL, 2.2 mmol) and quinoline-5-carbonyl chloride in30 mL THF were processed as in Example 134B to afford the title compound(0.18 g, 0.53 mmol, 49% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 2.30 (d,J=0.7 Hz, 3H), 2.34 (s, 3H), 3.31 (s, 3H), 3.80 (t, J=5.1 Hz, 2H), 4.49(t, J=5.3 Hz, 2H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.83 (dd, J=8.5, 7.1Hz, 1H), 8.15 (dt, J=8.5, 1.0 Hz, 1H), 8.40 (dd, J=7.3, 1.2 Hz, 1H),8.87 (dd, J=4.1, 1.7 Hz, 1H), 9.55 (ddd, J=8.8, 1.7, 0.7 Hz, 1H); MS(DCI/NH₃) m/z 342 (M+H)⁺; Anal. calculated for C₁₈H₁₉N₃O₂S: C, 63.32; H,5.61; N, 12.31. Found: C, 63.44; H, 5.05; N, 12.10.

Example 136N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]isoquinoline-5-carboxamide

The isoquinoline-5-carboxylic acid (Lancaster, 0.25 g, 1.4 mmol) wasconverted to the corresponding acid chloride with 5 mL of thionylchloride using the method described in Example 134A. The product ofExample 126A (0.20 g, 1.1 mmol), Et₃N (0.3 mL, 2.2 mmol) and the acidchloride in 30 mL THF were processed as in Example 134B to afford thetitle compound (98 mg, 0.29 mmol, 27% yield). ¹H NMR (300 MHz, CD₃OD) δppm 2.31 (s, 3H), 2.35 (s, 3H), 3.31 (s, 3H), 3.81 (t, J=5.3 Hz, 2H),4.50 (t, J=5.3 Hz, 2H), 7.76 (dd, J=7.5, 7.5 Hz, 1H), 8.23 (d, J=8.1 Hz,1H), 8.48 (d, J=6.4 Hz, 1H), 8.61 (dd, J=7.1, 1.4 Hz, 1H), 9.03 (d,J=6.1 Hz, 1H), 9.27 (d, J=1.0 Hz, 1H); MS (DCI/NH₃) m/z 342 (M+H)⁺;Anal. calculated for C₁₈H₁₉N₃O₂S: C, 63.32; H, 5.61; N, 12.31. Found: C,62.97; H, 5.54; N, 12.07.

Example 137N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2,3-dihydro-1-benzofuran-7-carboxamide

The 2,3-dihydrobenzofuran-7-carboxylic acid (TCI-US, 0.25 g, 1.4 mmol)was converted to 2,3-dihydrobenzofuran-7-carbonyl chloride with 5 mL ofthionyl chloride using the method described in Example 134A. The productof Example 126A (0.20 g, 1.1 mmol), Et₃N (0.3 mL, 2.2 mmol) and thefreshly prepared 2,3-dihydrobenzofuran-7-carbonyl chloride in 30 mL THFwere processed as in Example 134B. Purification of the crude materialvia recrystallization with 50% hexanes:EtOAc gave the title compound(0.12 g, 0.36 mmol, 34% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 2.25 (s,3H), 2.30 (s, 3H), 3.22 (t, J=8.8 Hz, 2H), 3.31 (s, 3H), 3.81 (t, J=5.3Hz, 2H), 4.44 (t, J=5.3 Hz, 2H), 4.64 (t, J=8.8 Hz, 2H), 6.86 (t, J=7.5Hz, 1H), 7.32 (dd, J=7.3, 1.2 Hz, 1H), 7.93 (dd, J=8.0, 0.8 Hz, 1H); MS(DCI/NH₃) m/z 333 (M+H)⁺; Anal. calculated for C₁₇H₂₀N₂O₃S.0.1H₂O: C,61.09; H, 6.09; N, 8.38. Found: C, 60.99; H, 5.91; N, 8.25.

Example 1382-chloro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]quinoline-4-carboxamide

The 2-chloroquinoline-4-carboxylic acid (TCI-JP, 0.29 g, 1.4 mmol) wasconverted to 2-chloroquinoline-4-carbonyl chloride with 5 mL of thionylchloride using the method described in Example 134A. The product ofExample 126A (0.20 g, 1.1 mmol), Et₃N (0.3 mL, 2.2 mmol) and2-chloroquinoline-4-carbonyl chloride in 30 mL THF were processed as inExample 134B to afford the title compound (0.14 g, 0.37 mmol, 35%yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 2.33 (s, 3H), 2.35 (s, 3H), 3.31(s, 3H), 3.78 (t, J=5.3 Hz, 2H), 4.49 (t, J=5.3 Hz, 2H), 7.66 (ddd,J=8.5, 7.1, 1.4 Hz, 1H), 7.81 (ddd, J=8.5, 7.1, 1.4 Hz, 1H), 7.94 (s,1H), 7.99 (dt, J=8.5, 0.7 Hz, 1H), 8.83 (dd, J=8.6, 1.2 Hz, 1H); MS(DCI/NH₃) m/z 376 (M+H)⁺; Anal. calculated for C₁₈H₁₈ClN₃O₂S: C, 57.52;H, 4.83; N, 11.18. Found: C, 57.44; H, 4.59; N, 10.97.

Example 139N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-1,2-dihydroacenaphthylene-5-carboxamide

The acenaphthene-5-carboxylic acid (Aldrich, 0.29 g, 1.4 mmol) in 5 mLof thionyl chloride was converted to acenaphthene-5-carbonyl chlorideusing the method described in Example 134A. The product of Example 126A(0.20 g, 1.1 mmol), Et₃N (0.3 mL, 2.2 mmol) and acenaphthene-5-carbonylchloride in 30 mL THF were processed as in Example 134B to afford thetitle compound (87 mg, 0.24 mmol, 22% yield). ¹H NMR (300 MHz, CD₃OD) δppm 2.28 (d, J=0.7 Hz, 3H), 2.33 (d, J=0.7 Hz, 3H), 3.33 (s, 3H), 3.42(s, 4H), 3.84 (t, J=5.3 Hz, 2H), 4.51 (t, J=5.3 Hz, 2H), 7.30-7.36 (m,2H), 7.52 (dd, J=8.6, 7.0 Hz, 1H), 8.43 (d, J=7.5 Hz, 1H), 8.81 (d,J=8.8 Hz, 1H); MS (DCI/NH₃) m/z 367 (M+H)⁺; Anal. calculated forC₂₁H₂₂N₂O₂S: C, 68.82; H, 6.05; N, 7.64. Found: C, 68.63; H, 5.72; N,7.40.

Example 1402,3-dichloro-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamideExample 140 A 3-(2-Methoxy-ethyl)-5-methyl-3H-thiazol-2-ylideneamine

The product of Example 10A (17.6 g, 70 mmol) was treated with ˜50 mL 20%aqueous K₂CO₃ then the mixture was extracted with EtOAc (3×25 mL). Thecombined organics were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound (5.9 g,34 mmol, 49% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 2.03 (d, J=1.70 Hz,3H) 3.36 (s, 3H) 3.62 (t, J=5.10 Hz, 2H) 3.83 (t, J=4.80 Hz, 2H)6.15-6.21 (m, 1H); MS (DCI/NH₃) m/z 173 (M+H)⁺.

Example 140B2,3-dichloro-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide

To the product of Example 140A (0.20 g, 1.2 mmol) in 15 mL THF was addedEt₃N (0.48 mL, 3.5 mmol) followed by a solution of 2,3-dichlorobenzoylchloride (Lancaster, 0.31 g, 1.5 mmol) in 5 mL THF. This mixture stirredat ambient temperature for 1 hour then was concentrated under reducedpressure, quenched with 5 mL saturated, aqueous NH₄Cl and extracted withEtOAc (3×5 mL). The combined organic extracts were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingsolids were recrystallized from 50% hexanes/EtOAc to afford the titlecompound (0.27 g, 0.78 mmol, 68% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm2.32 (d, J=1.4 Hz, 3H), 3.34 (s, 3H), 3.71 (t, J=5.1 Hz, 2H), 4.34 (t,J=4.8 Hz, 2H), 6.82-6.86 (m, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.49 (dd,J=8.1, 1.7 Hz, 1H), 7.73 (dd, J=7.5, 1.7 Hz, 1H); MS (DCI/NH₃) m/z 345(M+H)⁺; Anal. calculated for C₁₄H₁₄Cl₂N₂O₂S: C, 48.70; H, 4.09; N, 8.11.Found: C, 48.39; H, 3.70; N, 7.94.

Example 1415-chloro-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-(trifluoromethyl)benzamide

The product of Example 140A (0.20 g, 1.2 mmol), Et₃N (0.48 mL, 3.5 mmol)and 5-chloro-2-(trifluoromethyl)benzoyl chloride (Matrix, 0.31 g, 1.5mmol) in 20 mL THF were processed using the method described in Example140B to afford the title compound (0.16 g, 0.42 mmol, 36% yield). ¹H NMR(300 MHz, CDCl₃) δ ppm 2.33 (d, J=0.7 Hz, 3H), 3.34 (s, 3H), 3.69 (t,J=5.1 Hz, 2H), 4.34 (t, J=4.6 Hz, 2H), 6.85 (s, 1H), 7.42-7.48 (m, 1H),7.64 (d, J=8.5 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H); MS (DCI/NH₃) m/z 379(M+H)⁺; Anal. calculated for C₁₅H₁₄ClF₃N₂O₂S: C, 47.56; H, 3.73; N,7.40. Found: C, 47.31; H, 3.30; N, 7.33.

Example 1422-chloro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 126A (0.20 g, 1.1 mmol), Et₃N (0.45 mL, 3.2 mmol)and 2-chlorobenzoyl chloride (Aldrich, 0.26 g, 1.4 mmol) in 15 mL THFwere processed as in Example 132 to afford the title compound (0.13 g,0.40 mmol, 37% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 2.28 (s, 3H), 2.32(s, 3H), 3.31 (s, 3H), 3.76 (t, J=5.3 Hz, 2H), 4.42 (t, J=5.1 Hz, 2H),7.30-7.46 (m, 3H), 7.77-7.83 (m, 1H); MS (DCI/NH₃) m/z 325 (M+H)⁺; Anal.calculated for C₁₅H₁₇ClN₂O₂S: C, 55.46; H, 5.28; N, 8.62. Found: C,55.59; H, 4.81; N, 8.47.

Example 143N-[(2Z)-5-tert-butyl-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-ethoxybenzamideExample 143A5-tert-Butyl-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylideneamine

A mixture of 5-tert-butyl-4-methylthiazole-2-ylamine (1.5 g, 8.8 mmol)and 2-bromoethyl methyl ether (0.91 mL, 9.7 mmol) was warmed to 85° C.and allowed to stir for 24 hours. The crude material was dissolved in ˜5mL of a 1:1 mixture of CH₂Cl₂ and CH₃OH and a small amount of silica gelwas added. This mixture was concentrated to dryness and the residue waspurified via flash column chromatography (SiO₂, 9:1:0.1CH₂Cl₂:CH₃OH:NH₄OH) to afford the title compound (1.0 g, 4.4 mmol, 50%yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.41 (s, 9H) 2.38 (s, 3H) 3.35 (s,3H) 3.66 (t, J=4.70 Hz, 2H) 4.16 (t, J=4.70 Hz, 2H); MS (DCI/NH₃) m/z229 (M+H)⁺.

Example 143BN-[(2Z)-5-tert-butyl-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-ethoxybenzamide

A mixture of the product of Example 143A (0.15 g, 0.66 mmol), Et₃N (0.28mL, 2.0 mmol) and 2-ethoxybenzoyl chloride (Aldrich, 0.16 g, 0.86 mmol)in 15 mL THF were processed using the method described in Example 129 toafford the title compound (0.12 g, 0.33 mmol, 50% yield). ¹H NMR (300MHz, CD₃OD) δ ppm 1.41 (t, J=7.1 Hz, 3H), 1.45 (s, 9H), 2.47 (s, 3H),3.31 (s, 3H), 3.77 (t, J=5.3 Hz, 2H), 4.11 (q, J=6.8 Hz, 2H), 4.43 (t,J=5.3 Hz, 2H), 6.95 (dt, J=7.5, 1.0 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H),7.37 (ddd, J=8.7, 6.9, 1.7 Hz, 1H), 7.78 (dd, J=7.6, 1.9 Hz, 1H); MS(DCI/NH₃) m/z 377 (M+H)⁺; Anal. calculated for C₂₀H₂₈N₂O₃S: C, 63.80; H,7.50; N, 7.44. Found: C, 64.19; H, 7.44; N, 7.19.

Example 144N-[(2Z)-5-tert-butyl-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2,3-dichlorobenzamide

A mixture of the product of Example 143A (0.15 g, 0.66 mmol), Et₃N (0.28mL, 2.0 mmol) and 2,3-dichlorobenzoyl chloride (Lancaster, 0.18 g, 0.86mmol) in 15 mL THF were processed using the method described in Example129 to afford the title compound (0.11 g, 0.27 mmol, 42% yield). ¹H NMR(300 MHz, CDCl₃) δ ppm 1.43 (s, 9H), 2.43 (s, 3H), 3.30 (s, 3H), 3.74(t, J=5.3 Hz, 2H), 4.36 (t, J=5.3 Hz, 2H), 7.22 (dd, J=8.0, 8.0 Hz, 1H),7.48 (dd, J=8.1, 1.7 Hz, 1H), 7.72 (dd, J=7.6, 1.5 Hz, 1H); MS (DCI/NH₃)m/z 401 (M+H)⁺; Anal. calculated for C₁₈H₂₂Cl₂N₂O₂S: C, 53.87; H, 5.53;N, 6.98. Found: C, 53.86; H, 5.37; N, 6.76.

Example 145N-[(2Z)-5-tert-butyl-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(trifluoromethyl)benzamide

A mixture of the product of Example 143A (0.15 g, 0.66 mmol), Et₃N (0.28mL, 2.0 mmol) and 5-chloro-2-trifluoromethylbenzoyl chloride (Matrix,0.17 g, 0.86 mmol) in 15 mL THF were processed using the methoddescribed in Example 129 to afford the title compound (0.16 g, 0.37mmol, 56% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.46 (s, 9H), 2.49 (s,3H), 3.31 (s, 3H), 3.70 (t, J=5.3 Hz, 2H), 4.41 (t, J=5.3 Hz, 2H),7.56-7.62 (m, 1H), 7.71-7.76 (m, 2H); MS (DCI/NH₃) m/z 435 (M+H)⁺; Anal.calculated for C₁₉H₂₂ClF₃N₂O₂S: C, 52.47; H, 5.10; N, 6.44. Found: C,52.52; H, 4.94; N, 6.05.

Example 146N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-1-naphthamide

The product of Example 140A (0.20 g, 1.2 mmol), Et₃N (0.48 mL, 3.5 mmol)and 1-naphthoyl chloride (Aldrich, 0.22 g, 1.5 mmol) in 15 mL THF wereprocessed using the method described in Example 140B to afford the titlecompound (0.23 g, 0.69 mmol, 60% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm2.36 (d, J=1.0 Hz, 3H), 3.35 (s, 3H), 3.78 (t, J=5.4 Hz, 2H), 4.45 (t,J=5.1 Hz, 2H), 7.10-7.15 (m, 1H), 7.46-7.58 (m, 3H), 7.88-7.94 (m, 1H),7.97 (d, J=8.1 Hz, 1H), 8.17 (dd, J=7.3, 1.2 Hz, 1H), 8.83-8.90 (m, 1H);MS (DCI/NH₃) m/z 327 (M+H)⁺; Anal. calculated for C₁₈H₁₈N₂O₂S: C, 66.23;H, 5.56; N, 8.58. Found: C, 66.10; H, 5.64; N, 8.51.

Example 147N-[(2Z)-5-tert-butyl-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The 5-chloro-2-methoxybenzoic acid (Aldrich, 0.21 g, 1.1 mmol) wasconverted to 5-chloro-2-methoxybenzoyl chloride with 5 mL of thionylchloride using the method described in Example 134A. A mixture of theproduct of Example 143A (0.20 g, 0.88 mmol), Et₃N (0.48 mL, 3.4 mmol)and 5-chloro-2-methoxybenzoyl chloride in 15 mL THF were processed usingthe method described in Example 129 to afford the title compound (0.13g, 0.32 mmol, 37% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.41 (s, 9H),2.42 (s, 3H), 3.32 (s, 3H), 3.77 (t, J=5.3 Hz, 2H), 3.90 (s, 3H), 4.36(t, J=5.1 Hz, 2H), 6.90 (d, J=8.8 Hz, 1H), 7.31 (dd, J=8.8, 3.1 Hz, 1H),7.94 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 397 (M+H)⁺; Anal. calculatedfor C₁₉H₂₅ClN₂O₃S: C, 57.49; H, 6.35; N, 7.06. Found: C, 57.51; H, 6.30;N, 6.85.

Example 148N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methylbenzamide

The product of Example 140A (0.20 g, 1.2 mmol), Et₃N (0.48 mL, 3.5 mmol)and o-toloyl chloride (Aldrich, 0.23 g, 1.2 mmol) in 15 mL THF wereprocessed using the method described in Example 140B to afford the titlecompound (0.26 g, 0.90 mmol, 78% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm2.30 (s, 3H), 2.70 (s, 3H), 3.35 (s, 3H), 3.74 (t, J=5.1 Hz, 2H), 4.36(t, J=4.8 Hz, 2H), 6.77-6.81 (m, 1H), 7.23 (t, J=7.3 Hz, 2H), 7.28-7.35(m, 1H), 8.08-8.13 (m, 1H); MS (DCI/NH₃) m/z 291 (M+H)⁺; Anal.calculated for C₁₅H₁₈N₂O₂S: C, 62.04; H, 6.25; N, 9.65. Found: C, 62.40;H, 6.11; N, 9.70.

Example 1492,3-dichloro-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 149A5-Methyl-3-(tetrahydro-furan-2-ylmethyl)-3H-thiazol-2-ylideneamine

A mixture of 2-amino-5-methylthiazole (1.0 g, 8.7 mmol) and2-(bromomethyl)tetrahydrofuran (Maybridge, 1.1 mL, 10 mmol) was warmedto 85° C. and allowed to stir for 24 hours. The mixture was then cooledto ambient temperature and purified via column chromatography (SiO₂,9:1:0.1 CH₂Cl₂:CH₃OH:NH₄OH) to afford the title compound (1.5 g, 7.5mmol, 86% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.55-1.70 (m, 1H)1.89-2.01 (m, 2H) 2.07-2.20 (m, 1H) 2.28 (d, J=1.36 Hz, 3H) 3.72-3.82(m, 1H) 3.86-4.00 (m, 2H) 4.08-4.24 (m, 2H) 6.98-7.04 (m, 1H); MS(DCI/NH₃) m/z 199 (M+H)⁺.

Example 149B2,3-dichloro-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of the product of Example 149A (0.17 g, 0.86 mmol) in 10mL THF and 1 mL DMF was added Et₃N (0.36 mL, 2.6 mmol) followed by2,3-dichlorobenzoyl chloride (Lancaster, 0.27 g, 1.3 mmol). This mixturewas warmed to 50° C. and allowed to stir for 2 hours. The mixture wascooled to ambient temperature, diluted with 10 mL EtOAc, and quenchedwith 10 mL NH₄Cl. The layers were separated and the aqueous layer wasextracted 2×5 mL EtOAc. The combined organics were dried over anhydrousNa₂SO₄, filtered, concentrated under reduced pressure and purified viacolumn chromatography (SiO₂, 20% hexanes/EtOAc) to afford the titlecompound (0.24 g, 0.64 mmol, 75% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm1.58-1.68 (m, 1H), 1.78-1.94 (m, 2H), 2.00-2.13 (m, 1H), 2.32 (s, 3H),3.72-3.91 (m, 2H), 4.06-4.15 (m, 1H), 4.24 (ddd, J=14.0, 7.0, 2.7 Hz,1H), 4.47 (dd, J=13.6, 2.7 Hz, 1H), 6.91-6.95 (m, 1H), 7.22 (t, J=8.0Hz, 1H), 7.49 (dd, J=8.1, 1.7 Hz, 1H), 7.72 (dd, J=7.5, 1.7 Hz, 1H); MS(DCI/NH₃) m/z 371 (M+H)⁺; Anal. calculated for C₁₆H₁₆Cl₂N₂O₂S: C, 51.76;H, 4.34; N, 7.55. Found: C, 51.66; H, 4.17; N, 7.46.

Example 150N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-2-methylbenzamide

The product of Example 126A (0.20 g, 1.1 mmol), Et₃N (0.45 mL, 3.2 mmol)and o-toloyl chloride (Aldrich, 0.22 g, 1.4 mmol) in 15 mL THF wereprocessed using the method described in Example 129 to afford the titlecompound (0.15 g, 0.49 mmol, 46% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm2.23 (d, J=0.7 Hz, 3H), 2.26 (s, 3H), 2.70 (s, 3H), 3.31 (s, 3H), 3.77(t, J=5.3 Hz, 2H), 4.35 (t, J=5.3 Hz, 2H), 7.23 (t, J=7.5 Hz, 2H),7.27-7.35 (m, 1H), 8.08-8.14 (m, 1H); MS (DCI/NH₃) m/z 305 (M+H)⁺; Anal.calculated for C₁₆H₂₀N₂O₂S: C, 63.13; H, 6.62; N, 9.20. Found: C, 63.43;H, 6.53; N, 9.14.

Example 151N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 126A (0.20 g, 1.1 mmol), Et₃N (0.45 mL, 3.2 mmol)and benzoyl chloride (Aldrich, 0.16 mL, 1.4 mmol) in 15 mL THF wereprocessed using the method described in Example 129 to afford the titlecompound (0.11 g, 0.38 mmol, 35% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm2.24 (s, 3H), 2.27 (d, J=0.7 Hz, 3H), 3.32 (s, 3H), 3.82 (t, J=5.3 Hz,2H), 4.41 (t, J=5.3 Hz, 2H), 7.38-7.51 (m, 3H), 8.27-8.34 (m, 2H); MS(DCI/NH₃) m/z 291 (M+H)⁺; Anal: calculated for C₁₅H₁₈N₂O₂S: C, 62.04; H,6.25; N, 9.65. Found: C, 62.02; H, 6.05; N, 9.56.

Example 1522-chloro-4-fluoro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 126A (0.20 g, 1.1 mmol), Et₃N (0.37 mL, 2.7 mmol)and 2-chloro-4-fluorobenzene-1-carbonyl chloride (Acros, 0.25 g, 1.3mmol) in 15 mL THF were processed using the method described in Example132 to afford the title compound (0.19 g, 0.56 mmol, 52% yield). ¹H NMR(300 MHz, CDCl₃) δ ppm 2.24 (s, 3H), 2.27 (s, 3H), 3.30 (s, 3H), 3.76(t, J=5.1 Hz, 2H), 4.35 (t, J=5.1 Hz, 2H), 7.00 (ddd, J=8.5, 7.8, 2.4Hz, 1H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 8.04 (dd, J=8.8, 6.4 Hz, 1H); MS(DCI/NH₃) m/z 343 (M+H)⁺; Anal. calculated for C₁₅H₁₆ClFN₂O₂S: C, 52.55;H, 4.70; N, 8.17. Found: C, 52.60; H, 4.38; N, 8.06.

Example 1532-chloro-4-fluoro-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 140A (0.17 g, 1.0 mmol), Et₃N (0.35 mL, 2.5 mmol)and 2-chloro-4-fluorobenzene-1-carbonyl chloride (Acros, 0.23 g, 1.2mmol) in 15 mL THF were processed using the method described in Example140B to afford the title compound (0.15 g, 0.46 mmol, 46% yield). ¹H NMR(300 MHz, CDCl₃) δ ppm 2.32 (d, J=1.4 Hz, 3H), 3.35 (s, 3H), 3.73 (t,J=5.4 Hz, 2H), 4.36 (t, J=4.7 Hz, 2H), 6.80-6.84 (m, 1H), 7.00 (ddd,J=8.6, 7.8, 2.5 Hz, 1H), 7.16 (dd, J=8.6, 2.5 Hz, 1H), 8.04 (dd, J=8.8,6.4 Hz, 1H); MS (DCI/NH₃) m/z 329 (M+H)⁺; Anal. calculated forC₁₄H₁₄ClFN₂O₂S: C, 51.15; H, 4.29; N, 8.52. Found: C, 51.11; H, 3.90; N,8.43.

Example 1542,5-dichloro-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The 2,5-dichlorobenzoic acid (Aldrich, 0.28 g, 1.4 mmol) was convertedto 2,5-dichlorobenzoyl chloride with 5 mL of thionyl chloride using themethod described in Example 134A.

The product of Example 126A (0.20 g, 1.1 mmol), Et₃N (0.45 mL, 3.2 mmol)and 2,5-dichlorobenzoyl chloride in 15 mL THF were processed using themethod described in Example 132 to afford the title compound (0.10 g,0.28 mmol, 26% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 2.25 (d, J=1.0 Hz,3H), 2.28 (d, J=1.0 Hz, 3H), 3.31 (s, 3H), 3.76 (t, J=5.3 Hz, 2H), 4.36(t, J=5.3 Hz, 2H), 7.28 (d, J=2.4 Hz, 1H), 7.32-7.36 (m, 1H), 7.94 (d,J=2.4 Hz, 1H); MS (DCI/NH₃) m/z 359 (M+H)⁺; Anal. calculated forC₁₅H₁₆Cl₂N₂O₂S: C, 50.15; H, 4.49; N, 7.80. Found: C, 50.22; H, 4.15; N,7.63.

Example 1552,5-dichloro-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide

The 2,5-dichlorobenzoic acid (Aldrich, 0.28 g, 1.4 mmol) was convertedto 2,5-dichlorobenzoyl chloride with 5 mL of thionyl chloride using themethod described in Example 134A. The product of Example 140A (0.20 g,1.1 mmol), Et₃N (0.45 mL, 3.2 mmol) and 2,5-dichlorobenzoyl chloride in15 mL THF were processed using the method described in Example 129 toafford the title compound (0.24 g, 0.70 mmol, 65% yield). ¹H NMR (300MHz, CDCl₃) δ ppm 2.32 (d, J=1.4 Hz, 3H), 3.35 (s, 3H), 3.73 (t, J=5.1Hz, 2H), 4.37 (t, J=4.7 Hz, 2H), 6.83-6.86 (m, 1H), 7.28 (dd, J=8.5, 2.4Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.94 (d, J=2.7 Hz, 1H); MS (DCI/NH₃)m/z 345 (M+H)⁺; Anal. calculated for C₁₄H₁₄Cl₂N₂O₂S: C, 48.70; H, 4.09;N, 8.11. Found: C, 48.60; H, 3.78; N, 8.02.

Example 1565-chloro-2-methoxy-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide

The 5-chloro-2-methoxybenzoic acid (Aldrich, 0.28 g, 1.5 mmol) wasconverted to 5-chloro-2-methoxybenzoyl chloride with 5 mL of thionylchloride using the method described in Example 134A. The product ofExample 140A (0.19 g, 1.1 mmol), Et₃N (0.45 mL, 3.2 mmol) and5-chloro-2-methoxybenzoyl chloride in 15 mL THF were processed using themethod described in Example 129 to afford the title compound (0.25 g,0.72 mmol, 67% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 2.30 (d, J=1.0 Hz,3H), 3.36 (s, 3H), 3.74 (t, J=5.1 Hz, 2H), 3.90 (s, 3H), 4.36 (t, J=4.7Hz, 2H), 6.82 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.33 (dd, J=8.8, 2.7 Hz,1H), 7.96 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 341 (M+H)⁺; Anal.calculated for C₁₅H₁₇ClN₂O₃S: C, 52.86; H, 5.03; N, 8.22. Found: C,52.84; H, 4.72; N, 8.13.

Example 1572,3-dichloro-N-[(2Z)-5-methyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 157A5-Methyl-3-(tetrahydro-pyran-2-ylmethyl)-3H-thiazol-2-ylideneamine

A mixture of 2-amino-5-methylthiazole (1.2 g, 10.5 mmol) and2-(bromomethyl)tetrahydro-2H-pyran (Aldrich, 1.5 mL, 11.6 mmol) waswarmed to 85° C. and allowed to stir for 18 hours. The mixture wascooled to ambient temperature and purified by flash columnchromatography (SiO₂, first 10% CH₃OH:EtOAc then 9:1:0.1CH₂Cl₂:CH₃OH:NH₄OH) to afford the title compound (1.1 g, 5.2 mmol, 49%yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.12-1.32 (m, 1H) 1.44-1.63 (m,2H) 1.79-1.95 (m, 2H) 2.06 (d, J=12.89 Hz, 1H) 2.25 (d, J=1.36 Hz, 3H)3.33-3.45 (m, 1H) 3.65-3.78 (m, 1H) 3.86-4.01 (m, 2H) 4.44 (dd, J=14.92,2.03 Hz, 1H) 6.56-6.65 (m, 1H) 9.48 (s, 1H); MS (DCI/NH₃) m/z 213(M+H)⁺.

Example 157B2,3-dichloro-N-[(2Z)-5-methyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 157A (0.15 g, 0.71 mmol), Et₃N (0.30 mL, 2.1mmol) and 2,3-dichlorobenzoyl chloride (Lancaster, 0.19 g, 0.92 mmol) in15 mL THF were processed as in Example 129 to afford the title compound(0.14 g, 0.36 mmol, 51% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.16-1.33(m, 1H), 1.46-1.56 (m, 3H), 1.64-1.73 (m, 1H), 1.80-1.92 (m, 1H), 2.32(d, J=1.4 Hz, 3H), 3.30-3.43 (m, 1H), 3.69 (qt, J=11.5, 8.8, 2.0 Hz,1H), 3.91-4.01 (m, 2H), 4.41 (dd, J=13.9, 2.7 Hz, 1H), 6.86 (d, J=1.4Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.49 (dd, J=8.0, 1.5 Hz, 1H), 7.74 (dd,J=7.6, 1.5 Hz, 1H); MS (DCI/NH₃) m/z 385 (M+H)⁺; Anal. calculated forC₁₇H₁₈Cl₂N₂O₂S: C, 52.99; H, 4.71; N, 7.27. Found: C, 53.15; H, 4.72; N,7.14.

Example 1582-ethoxy-N-[(2Z)-5-methyl-3-(tetrahhydro-2H-pyran-2-ylmethyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 157A (0.15 g, 0.71 mmol), Et₃N (0.30 mL, 2.1mmol) and 2-ethoxybenzoyl chloride (Aldrich, 0.18 g, 0.92 mmol) in 15 mLTHF were processed as in Example 129 to afford the title compound (0.14g, 0.39 mmol, 55% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.20-1.32 (m,1H), 1.46 (t, J=7.0 Hz, 3H), 1.50-1.54 (m, 3H), 1.63-1.79 (m, 1H),1.80-1.90 (m, 1H), 2.29 (s, 3H), 3.32-3.43 (m, 1H), 3.64-3.76 (m, 1H),3.92-4.00 (m, 2H), 4.16 (q, J=6.8 Hz, 2H), 4.37-4.47 (m, 1H), 6.76-6.84(m, 1H), 6.93-7.00 (m, 2H), 7.35 (t, J=8.1 Hz, 1H), 7.96 (dd, J=8.0, 1.9Hz, 1H); MS (DCI/NH₃) m/z 361 (M+H)⁺; Anal. calculated for C₁₉H₂₄N₂O₃S:C, 63.61; H, 6.71; N, 7.77. Found: C, 63.56; H, 6.73; N, 7.26.

Example 1595-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

The 5-chloro-2-methoxybenzoic acid (Aldrich, 0.66 g, 3.5 mmol) wasconverted to 5-chloro-2-methoxybenzoyl chloride with 5 mL of thionylchloride using the method described in Example 134A. The product ofExample 149A (0.35 g, 0.18 mmol), Et₃N (0.74 mL, 5.3 mmol) and5-chloro-2-methoxybenzoyl chloride in 20 mL THF were processed using themethod described in Example 149B to afford the title compound (0.25 g,0.68 mmol, 20% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.67-1.78 (m, 1H),1.84-1.96 (m, 2H), 2.00-2.13 (m, 1H), 2.34 (d, J=1.4 Hz, 3H), 3.71-3.81(m, 1H), 3.85 (s, 3H), 3.86-3.93 (m, 1H), 4.20-4.42 (m, 3H), 7.07 (d,J=9.2 Hz, 1H), 7.12-7.16 (m, 1H), 7.39 (dd, J=8.8, 2.7 Hz, 1H), 7.81 (d,J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 367 (M+H)⁺; Anal. calculated forC₁₇H₁₉ClN₂O₃S.0.2H₂O: C, 55.12; H, 5.28; N, 7.56. Found: C, 54.90; H,4.95; N, 7.55.

Example 1605-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

The 5-chloro-2-methoxybenzoic acid (Aldrich, 0.17 g, 0.92 mmol) wasconverted to 5-chloro-2-methoxybenzoyl chloride with 5 mL of thionylchloride using the method described in Example 134A. A mixture of theproduct of Example 157A (0.15 g, 0.71 mmol), Et₃N (0.30 mL, 2.1 mmol)and 5-chloro-2-methoxybenzoyl chloride in 15 mL THF were processed usingthe method described in Example 129 to afford the title compound (0.11g, 0.29 mmol, 41% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.20-1.36 (m,1H), 1.48-1.61 (m, 3H), 1.66-1.76 (m, 1H), 1.83-1.92 (m, 1H), 2.30 (d,J=1.0 Hz, 3H), 3.33-3.44 (m, 1H), 3.67-3.77 (m, 1H), 3.90 (s, 3H),3.93-4.05 (m, 2H), 4.40 (dd, J=13.9, 2.4 Hz, 1H), 6.83 (s, 1H), 6.90 (d,J=8.8 Hz, 1H), 7.32 (dd, J=8.8, 2.7 Hz, 1H), 7.97 (d, J=2.7 Hz, 1H); MS(DCI/NH₃) m/z 381 (M+H)⁺; Anal. calculated for C₁₈H₂₁ClN₂O₃S.0.15H₂O: C,56.36; H, 5.60; N, 7.30. Found: C, 56.70; H, 5.41; N, 6.91.

Example 1612-ethoxy-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 149A (0.20 g, 1.0 mmol), Et₃N (0.42 mL, 3.0 mmol)and the 2-ethoxybenzoyl chloride (Aldrich, 0.23 mL, 1.5 mmol) in 15 mLTHF were processed using the method described in Example 149B to affordthe title compound (0.18 g, 0.52 mmol, 52% yield). ¹H NMR (300 MHz,CD₃OD) δ ppm 1.40 (t, J=7.0 Hz, 3H), 1.64-1.75 (m, 1H), 1.83-1.94 (m,2H), 2.00-2.12 (m, 1H), 2.33 (d, J=1.4 Hz, 3H), 3.70-3.80 (m, 1H),3.83-3.93 (m, 1H), 4.11 (q, J=7.1 Hz, 2H), 4.18-4.27 (m, 1H), 4.28-4.42(m, 2H), 6.96 (dt, J=7.5, 1.0 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 7.09-7.13(m, 1H), 7.38 (ddd, J=8.4, 7.4, 1.9 Hz, 1H), 7.77 (dd, J=7.6, 1.9 Hz,1H); MS (DCI/NH₃) m/z 347 (M+H)⁺; Anal. calculated forC₁₈H₂₂N₂O₃S.0.1H₂O: C, 62.40; H, 6.40; N, 8.09. Found: C, 63.49; H,5.90; N, 7.84.

Example 1625-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(tetrahydrofuran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 162A Toluene-4-sulfonic acid tetrahydro-furan-3-ylmethyl ester

To a solution of tetrahydro-3-furanmethanol (Aldrich, 1.0 mL, 10.4 mmol)in 5 mL CH₂Cl₂ and 5 mL pyridine was added para-toluenesulfonyl chloride(3.0 g, 15.6 mmol) portion-wise over 15 minutes. This mixture stirred atambient temperature for 3 hours then 5 mL H₂O was added. The layers wereseparated and the aqueous layer was extracted 2×5 mL CH₂Cl₂. Thecombined organics were dried over Na₂SO₄, filtered, concentrated underreduced pressure and dried under vacuum (˜1 mm Hg) to afford the titlecompound (2.62 g, 10.2 mmol, 98% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm1.49-1.63 (m, 1H) 1.94-2.08 (m, 1H) 2.46 (s, 3H) 2.52-2.68 (m, 1H) 3.49(dd, J=9.16, 5.09 Hz, 1H) 3.64-3.84 (m, 3H) 3.88-4.03 (m, 2H) 7.36 (d,J=8.14 Hz, 2H) 7.76-7.82 (m, 2H); MS (DCI/NH₃) m/z 257 (M+H)⁺.

Example 162B5-Methyl-3-(tetrahydro-furan-3-ylmethyl)-3H-thiazol-2-ylideneamine

A mixture of the product of Example 162A (1.62 g, 6.3 mmol),2-amino-5-methylthiazole (0.72 g, 6.3 mmol) and LiBr (55 mg, 0.63 mmol)in 2 mL DMF was warmed to 85° C. and allowed to stir for 16 hours. Themixture was then allowed to cool to ambient temperature, diluted with 10mL CH₂Cl₂ and washed with 1×5 mL 10% aqueous Na₂CO₃ solution. The layerswere separated and the aqueous layer was extracted 2×5 mL CH₂Cl₂. Thecombined organics were dried over anhydrous Na₂SO₄, filtered,concentrated under reduced pressure and purified by columnchromatography (SiO₂, 9:1:0.1 CH₂Cl₂:CH₃OH:NH₄OH) to afford the titlecompound (0.31 g, 1.6 mmol, 25% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm1.61-1.74 (m, 1H) 1.96-2.04 (m, 1H) 2.05 (d, J=1.36 Hz, 3H) 2.69-2.84(m, 1H) 3.53 (dd, J=8.82, 5.76 Hz, 1H) 3.63 (dd, J=7.63, 2.20 Hz, 2H)3.69-3.81 (m, 2H) 3.89 (ddd, J=8.31, 5.42 Hz, 1H) 6.36-6.42 (m, 1H); MS(DCI/NH₃) m/z 199 (M+H)⁺.

Example 162C5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(tetrahydrofuran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

The 5-chloro-2-methoxybenzoic acid (Aldrich, 0.40 g, 2.1 mmol) wasconverted to 5-chloro-2-methoxybenzoyl chloride with 5 mL of thionylchloride using the method described in Example 134A. The product ofExample 162B (0.21 g, 1.1 mmol), Et₃N (0.44 mL, 3.2 mmol) and5-chloro-2-methoxybenzoyl chloride in 15 mL THF were processed using themethod described in Example 149B to afford the title compound (0.28 g,0.76 mmol, 72% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.69-1.83 (m, 1H),1.96-2.09 (m, 1H), 2.34 (d, J=1.4 Hz, 3H), 2.84-3.00 (m, 1H), 3.64 (dd,J=8.8, 5.1 Hz, 1H), 3.72-3.81 (m, 2H), 3.85 (s, 3H), 3.89-3.99 (m, 1H),4.17-4.33 (m, 2H), 7.06 (d, J=8.8 Hz, 1H), 7.14-7.17 (m, 1H), 7.39 (dd,J=8.8, 2.7 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 367 (M+H)⁺;Anal. calculated for C₁₇H₁₉ClN₂O₃S: C, 55.66; H, 5.22; N, 7.64. Found:C, 55.77; H, 4.85; N, 7.26.

Example 1632-ethoxy-N-[(2Z)-5-methyl-3-(tetrahydrofuran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 162B (0.17 g, 0.86 mmol), Et₃N (0.36 mL, 2.6mmol) and the 2-ethoxybenzoyl chloride (Aldrich, 0.15 mL, 0.94 mmol) in10 mL THF were processed using the method described in Example 149B toafford the title compound (0.26 g, 0.74 mmol, 86% yield). ¹H NMR (300MHz, CD₃OD) δ ppm 1.39 (t, J=7.0 Hz, 3H), 1.68-1.82 (m, 1H), 1.92-2.05(m, 1H), 2.34 (d, J=1.4 Hz, 3H), 2.85-3.02 (m, 1H), 3.63 (dd, J=8.8, 5.4Hz, 1H), 3.70-3.80 (m, 2H), 3.88-3.97 (m, 1H), 4.12 (q, J=6.9 Hz, 2H),4.17-4.33 (m, 2H), 6.96 (dt, J=7.5, 1.0 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H),7.11-7.16 (m, 1H), 7.38 (ddd, J=8.6, 7.0, 1.7 Hz, 1H), 7.79 (dd, J=7.8,1.7 Hz, 1H); MS (DCI/NH₃) m/z 347 (M+H)⁺; Anal. calculated forC₁₈H₂₂N₂O₃S: C, 62.40; H, 6.40; N, 8.09. Found: C, 62.43; H, 6.29; N,7.96.

Example 1642-ethoxy-N-[(2Z)-3-[2-(2-methoxyethoxy)ethyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamideExample 164A3-[2-(2-Methoxyethoxy)ethyl]-5-methyl-1,3-thiazol-2(3H)-ylideneamine

A mixture of 2-amino-5-methylthiazole (1.5 g, 13.0 mmol) and1-bromo-2-(2-methoxyethoxy)ethane (Aldrich, 2.0 mL, 14.5 mmol) wasprocessed as in Example 157A to afford the title compound (2.2 g, 10.9mmol, 78% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 2.29 (d, J=1.36 Hz, 3H)3.34 (s, 3H) 3.49-3.54 (m, 2H) 3.60-3.66 (m, 2H) 3.80 (t, J=5.10 Hz, 2H)4.13 (t, J=4.80 Hz, 2H) 6.99-7.04 (m, 1H); MS (DCI/NH₃) m/z 217 (M+H)⁺.

Example 164B2-ethoxy-N-[(2Z)-3-[2-(2-methoxyethoxy)ethyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 164A (0.22 g, 1.0 mmol), Et₃N (0.23 mL, 2.0 mmol)and 2-ethoxybenzoyl chloride (Aldrich, 0.25 g, 1.3 mmol) in 15 mL THFwere processed as in Example 129 to afford the title compound (0.15 g,0.40 mmol, 40% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.40 (t, J=7.0 Hz,3H), 2.33 (d, J=1.4 Hz, 3H), 3.31 (s, 3H), 3.46-3.51 (m, 2H), 3.58-3.63(m, 2H), 3.85 (t, J=5.3 Hz, 2H), 4.11 (q, J=6.8 Hz, 2H), 4.40 (t, J=5.3Hz, 2H), 6.96 (dt, J=7.5, 1.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 7.11-7.15(m, 1H), 7.38 (ddd, J=8.4, 7.4, 1.9 Hz, 1H), 7.79 (dd, J=7.6, 1.9 Hz,1H); MS (DCI/NH₃) m/z 365 (M+H)⁺; Anal. calculated for C₁₈H₂₄N₂O₄S: C,59.88; H, 6.86; N, 7.51. Found: C, 60.05; H, 6.81; N, 7.60.

Example 1662,3-dichloro-N-[(2Z)-3-[2-(2-methoxyethoxy)ethyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 164A (0.22 g, 1.0 mmol), Et₃N (0.23 mL, 2.0 mmol)and 2,3-dichlorobenzoyl chloride (Lancaster, 0.27 g, 1.3 mmol) in 15 mLTHF were processed as in Example 129 to afford the title compound (95mg, 0.24 mmol, 24% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 2.36 (d, J=1.4Hz, 3H), 3.31 (s, 3H), 3.46-3.50 (m, 2H), 3.57-3.62 (m, 2H), 3.83 (t,J=5.4 Hz, 2H), 4.40 (t, J=5.1 Hz, 2H), 7.18-7.21 (m, 1H), 7.33 (t, J=7.8Hz, 1H), 7.58 (dd, J=8.0, 1.5 Hz, 1H), 7.64 (dd, J=7.6, 1.5 Hz, 1H); MS(DCI/NH₃) m/z 389 (M+H)⁺; Anal. calculated for C₁₆H₁₈Cl₂N₂O₃S: C, 49.36;H, 4.66; N, 7.20. Found: C, 48.98; H, 4.60; N, 6.99.

Example 1675-chloro-2-methoxy-N-[(2Z)-3-[2-(2-methoxyethoxy)ethyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide

The 5-chloro-2-methoxybenzoic acid (Aldrich, 0.24 g, 1.3 mmol) wasconverted to the 5-chloro-2-methoxybenzoyl chloride with 5 mL of thionylchloride using the method described in Example 134A. The product ofExample 164A (0.22 g, 1.0 mmol), Et₃N (0.42 mL, 3.0 mmol) and5-chloro-2-methoxybenzoyl chloride in 15 mL THF were processed using themethod described in Example 129 to afford the title compound (0.21 g,0.55 mmol, 55% yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 2.34 (d, J=1.4 Hz,3H), 3.31 (s, 3H), 3.47-3.52 (m, 2H), 3.59-3.64 (m, 2H), 3.86 (s, 3H),3.88 (t, J=5.4 Hz, 2H), 4.41 (t, J=4.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H),7.14-7.17 (m, 1H), 7.39 (dd, J=9.0, 2.9 Hz, 1H), 7.83 (d, J=2.7 Hz, 1H);MS (DCI/NH₃) m/z 385 (M+H)⁺; Anal. calculated for C₁₇H₂₁ClN₂O₄S: C,53.05; H, 5.50; N, 7.28. Found: C, 52.93; H, 5.61; N, 7.26.

Example 1682-methoxy-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

The product of Example 149A (0.15 g, 0.76 mmol), Et₃N (0.32 mL, 2.3mmol) and the o-anisoyl chloride (Aldrich, 0.15 mL, 1.1 mmol) in 10 mLTHF were processed using the method described in Example 149B to affordthe title compound (88 mg, 0.26 mmol, 35% yield). ¹H NMR (300 MHz,CD₃OD) δ ppm 1.66-1.76 (m, 1H), 1.84-1.95 (m, 2H), 2.02-2.12 (m, 1H),2.33 (d, J=1.4 Hz, 3H), 3.71-3.79 (m, 1H), 3.85 (s, 3H), 3.84-3.92 (m,1H), 4.22-4.28 (m, 1H), 4.29-4.41 (m, 2H), 6.98 (dt, J=7.6, 1.0 Hz, 1H),7.07 (dd, J=8.5, 1.0 Hz, 1H), 7.10-7.12 (m, 1H), 7.42 (ddd, J=9.2, 7.5,2.0 Hz, 1H), 7.85 (dd, J=7.8, 1.7 Hz, 1H); MS (DCI/NH₃) m/z 333 (M+H)⁺;Anal. calculated for C₁₇H₂₀N₂O₃S: C, 61.42; H, 6.06; N, 8.43. Found: C,61.35; H, 6.10; N, 8.28.

Example 1691-(1,1-Dimethylpropyl)-3-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]ureahydrochloride Example 169A1-(1,1-Dimethylpropyl)-3-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]urea

To a solution of 1,1-dimethylpropylamine (174 mg, 2.0 mmole) in 19 mL ofTHF and 1 mL of N,N-diisopropylethyl amine was added 4-nitrophenylchloroformate (403 mg, 2.0 mmole). The solution was irradiated in asealed tube placed in a single node microwave at 70° C. for 300 sec(maximum power 300 W) with stirring. The resulting solution was cooledto room temperature and3-(2-methoxyethyl)-4,5-dimethyl-3H-thiazol-2-ylideneamine hydrobromide(587 mg, 2.2 mmole) from Example 12A was added. The sealed tube wasirradiated at 120° C. for 1800 sec with stirring. The mixture was cooledand the volatile components were removed under reduced pressure. Theresidue was partitioned between water and ethyl acetate. The phases wereseparated and organic extract was dried over anhydrous Na₂SO₄, filtered,and concentrated. Purification by column chromatography (SiO₂, 0-70%ethyl acetate/hexanes gradient) afforded the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 0.76 (t, J=7 Hz, 3H) 1.20 (s, 6H) 1.66 (d, J=7 Hz,2H) 2.06 (s, 3H) 2.11 (s, 3H) 3.30 (s, 3H) 3.55 (t, J=5 Hz, 2H) 4.06 (t,J=5 Hz, 2H) 6.13 (s, 1H)), MS (DCI/NH₃) m/z 300 (M+H)⁺.

Example 169B1-(1,1-Dimethylpropyl)-3-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]ureahydrochloride

To a solution of the product from Example 169A in Me0H was added asolution of HC1 in Et₂O. The title compound was isolated by filtration.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (t, J=7 Hz, 3H) 1.26 (s, 6H) 1.65(q, J=7 Hz, 2H) 2.24 (s, 6H) 3.24 (s, 3H) 3.64 (t, J=5 Hz, 2H) 4.45 (s,2H), MS (DCI/NH₃) m/z 300 (M+H)⁺. Anal. Calculated for C₁₄H₂₅ClN₃O₂S: C,50.06; H, 7.80; N, 12.51. Found: C, 50.11; H, 7.87; N, 12.35.

Example 1701-(1,1-Dimethyl-propyl)-3-[(2Z)-3-(2-methoxyethyl)-1,3-benzothiazol-2(3H)-ylidene]urea

To a solution of 1,1-dimethyl-propylamine (0.60 mL, 5.2 mmol) andtriethylamine (0.40 mL, 2.9 mmol) in 12 mL of a 1:1 mixture of THF:DMFat 0° C. was added p-nitrophenylchloroformate (0.58 g, 2.9 mmol). After30 minutes, the product of Example 64A (0.75 g, 2.6 mmol) and anotheraliquot of triethylamine (0.40 mL, 2.9 mmol) were added and the solutionstirred at ambient temperature for 9 hours. The mixture was diluted withethyl acetate then washed twice with water and brine. The organicextract was dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. Purification by column chromatography (SiO₂,20-40% ethyl acetate/hexanes gradient) afforded 0.06 g (8%) of the titlecompound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 0.91 (t, J=7.46 Hz, 3H), 1.39(s, 6H), 1.78 (q, J=7.46 Hz, 2H), 3.28 (s, 3H), 3.86 (t, J=4.92 Hz, 2H),4.82 (t, J=4.58 Hz, 2H), 7.46 (t, J=7.63 Hz, 1H), 7.58 (t, J=7.63 Hz,1H), 7.64-7.70 (m, 1H), 7.75 (d, J=7.80 Hz, 1H), 9.06 (s, 1H). MS(DCI/NH₃) m/z 322 (M+H)⁺.

Example 1711-[(2Z)-3-(2-Methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-3-(3,3,5,5-tetramethylcyclohexyl)urea

The product of Example 12A and 3,3,5,5-tetramethylcyclohexylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.90 (s, 6H) 1.02 (s, 6H)1.17-1.27 (m, 1H) 1.61 (d, J=12 Hz, 1H) 2.18-2.27 (m, 6H) 3.24 (s, 3H)3.62 (t, J=5 Hz, 2H) 3.76-3.87 (m, J=5 Hz, 2H) 3.98 (s, 2H) 4.40 (s,2H), MS (DCI/NH₃) m/z 366 (M+H)⁺. Anal. Calculated forC₁₉H₁₄ClN₃O₂S.0.7CH₄O: C, 55.49; H, 8.7; N, 9.85. Found C, 55.81; H,8.37; N, 9.52.

Example 1721-[(2Z)-3-(2-Methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]-3-(1-methyl-3-phenylpropyl)urea

The product of Example 12A and 1-methyl-3-phenylpropylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.13 (d, J=6 Hz, 3H) 1.60-1.82(m, 2H) 2.18 (s, 3H) 2.20 (s, 3H) 2.55-2.68 (m, 2H) 3.25 (s, 3H)3.53-3.80 (m, 3H) 4.31 (s, 2H) 7.08-7.35 (m, 5H), MS (DCI/NH₃) m/z 362(M+H)⁺.

Example 173 ethylN-({[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-L-leucinate

The product of Example 12A and (2S)-ethyl-2-amino-4-methylpentanoatewere processed using the method described in Example 169A to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.87 (dd, J=9, 6 Hz, 6H)1.37-1.50 (m, 1H) 1.51-1.65 (m, 2H) 1.84 (s, 3H) 2.17 (s, 3H) 2.21 (s,3H) 3.22-3.23 (m, 3H) 3.62 (t, J=5 Hz, 2H) 4.18-4.33 (m, 2H) 4.37-4.48(m, 1H) 7.88 (d, J=9 Hz, 1H)), MS (DCI/NH₃) m/z 342 (M+H)⁺. Anal.Calculated for C₁₆H₂₇N₃O₃S: C, 56.26; H, 7.97; N, 12.31. Found C, 56.20;H, 8.04; N, 12.31.

Example 1741-(1,1-Dimethylpropyl)-3-[(2Z)-5-methyl-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 157A and 2,2-dimethylpropylamine were processedusing the method described in Example 169A to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.76 (t, 3H) 1.12-1.17 (m, 1H) 1.20 (s,6H) 1.38-1.49 (m, J=3 Hz, 3H) 1.50-1.59 (m, 1H) 1.66 (q, J=7 Hz, 2H)1.75-1.82 (m, 1H) 2.12 (s, 3H) 3.22-3.30 (m, 1H) 3.54-3.65 (m, 1H)3.80-3.93 (m, 3H) 6.19 (s, 1H) 6.79 (s, 1H), MS (DCI/NH₃) m/z 326(M+H)⁺. Anal. Calculated for C₁₆H₂7N₃O₂S: C, 59.04; H, 8.36; N, 12.91.Found C, 59.06; H, 8.36; N, 12.91.

Example 1751-(1,2-Dimethyl-propyl)-3-[(2Z)-5-methyl-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]ureahydrochloride

The product of Example 157A and 1,2-dimethylpropylamine were processedaccording to the method described in Example 169A to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.81 (dd, J=7, 3 Hz, 1H)0.84-0.96 (m, 6H) 1.06 (d, J=7 Hz, 3H) 1.20 (t, 1H) 1.34-1.54 (m, 3H)1.60-1.76 (m, 1H) 1.69-1.95 (m, 2H) 2.28 (s, 3H) 3.22-3.37 (m, 1H) 3.84(d, J=11 Hz, 2H) 4.10-4.30 (m, 1H) 4.31-4.47 (m, 1H) 7.23-7.41 (m, 1H)7.83-8.06 (m, 1H),), MS (DCI/NH₃) m/z 326 (M+H)⁺. Anal. Calculated forC₁₆H₂₈ClN₃O₂S: C, 53.10; H, 7.80; N, 11.16. Found C, 52.73; H, 7.96; N,10.82.

Example 1761-Cyclohexyl-3-[(2Z)-4,5-dimethyl-3-tetrahydropyran-2-ylmethyl-1,3-thiazol-2(3H)-lidene]ureaExample 176A4,5-Dimethyl-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylideneaminehydrobromide

A mixture of 2-amino-4,5-dimethylthiazole and2-(bromomethyl)tetrahydro-2H-pyran were processed using the methoddescribed in Example 12A to afford the title compound ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.13-1.31 (m, 1H) 1.36-1.52 (m, 3H) 1.64-1.85 (m, 2H)2.18 (d, J=4 Hz, 6H) 3.19-3.33 (m, 1H) 3.49-3.63 (m, 1H) 3.77-3.89 (m,1H) 3.94-4.02 (m, 2H) 9.34 (s, 2H),), MS (DCI/NH₃) m/z 227 (M+H)⁺.

Example 176B1-Cyclohexyl-3-[(2Z)-4,5-dimethyl-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 176A and cyclohexylamine were processed using themethod described in Example 169A to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.05-1.29 (m, 6H) 1.37-1.49 (m, 3H) 1.51-1.63(m, 2H) 1.76 (m, 5H) 2.06 (s, 3H) 2.11 (s, 3H) 3.19-3.30 (m, 1H)3.56-3.68 (m, 1H) 3.70-3.88 (m, 3H) 3.99 (dd, J=14, 3 Hz, 1H) 6.59 (d,J=8 Hz, 1H),), MS (DCI/NH₃) m/z 352 (M+H)⁺. Anal. Calculated forC₁₈H₂9N₃O₂S.0.1H₂O: C, 61.19; H, 8.33 N, 11.89. Found C, 61.03; H, 8.45;N, 11.69.

Example 1771-(4-Methylcyclohexyl)-3-[(2Z)-5-methyl-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 157A and 4-methylcyclohexylamine were processedusing the method described in Example 169A to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.88 (dd, J=12, 7 Hz, 3H) 0.96 (d, J=3Hz, 1H) 1.09-1.31 (m, 3H) 1.31-1.70 (m, 9H) 1.69-1.85 (m, 2H) 2.12 (s,3H) 3.21-3.29 (m, 1H) 3.55-3.64 (m, J=3 Hz, 2H) 3.79-3.95 (m, 3H) 6.62(t, J=8 Hz, 1H) 6.77-6.81 (m, J=1 Hz, 1H), MS (DCI/NH₃) m/z 352 (M+H)⁺.

Example 1781-(1,1-Dimethylpropyl)-3-[(2Z)-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]ureaExample 178A3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylideneaminehydrobromide

A mixture of 2-aminothiazole and 2-(bromomethyl)tetrahydro-2H-pyran wereprocessed using the method described in Example 12A to afford the titlecompound. MS (DCI/NH₃) m/z 199 (M+H)⁺

Example 178B1-(1,1-Dimethylpropyl)-3-[(2Z)-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 178A and 1,1-dimethylpropylamine were processedusing the method described in Example 169A to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.77 (t, J=7 Hz, 3H) 1.14-1.19 (m, 1H)1.21 (s, 6H) 1.39-1.49 (m, 3H) 1.50-1.59 (m, 1H) 1.61-1.72 (m, 2H) 1.79(s, 1H) 3.19-3.28 (m, 1H) 3.56-3.68 (m, 1H) 3.78-3.89 (m, 1H) 3.92-4.02(m, 2H) 6.23 (s, 1H) 6.55 (d, J=5 Hz, 1H) 7.08 (d, J=5 Hz, 1H), MS(DCI/NH₃) m/z 312 (M+H)⁺. Anal. Calculated for C₁₅H₂₅N₃O₂S: C, 57.85; H,8.09; N, 13.49 Found C, 58.01; H, 8.23; N, 13.30.

Example 179N-[(2Z)-4,5-dimethyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-N′-[(1S)-1,2,2-trimethylpropyl]urea

The product of Example 176A and (1S)-1,2,2-trimethylpropylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (s, 9H) 0.98 (d, J=7 Hz,3H) 1.12-1.28 (m, 1H) 1.40-1.49 (m, 3H) 1.47-1.64 (m, J=13 Hz, 1H)1.73-1.84 (m, 1H) 2.12 (s, 3H) 3.23-3.30 (m, 1H) 3.50-3.68 (m, 2H)3.80-4.03 (m, 3H) 6.46 (dd, J=9, 3 Hz, 1H) 6.80 (dd, J=5, 2 Hz, 1H), MS(DCI/NH₃) m/z 354 (M+H)⁺. Anal. Calculated for C₁₈H₃₁N₃O₂S: C, 61.15; H,8.84; N, 11.69. Found C, 60.80; H, 8.88; N, 11.69.

Example 1801-(2,2-Dimethylpropyl)-3-[(2Z)-4,5-dimethyl-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 176A and 2,2-dimethylpropylamine were processedusing the method described in Example 169A to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (s, 9H) 1.16-1.28 (m, 1H) 1.45 (s,3H) 1.56-1.68 (m, 1H) 1.76-1.87 (m, 1H) 2.06 (s, 3H) 2.11 (s, 3H)2.77-2.87 (m, 1H) 2.90-3.02 (m, 1H) 3.15-3.28 (m, 1H) 3.60-3.70 (m, 1H)3.72-3.86 (m, 2H) 3.94-4.11 (m, 1H) 6.58-6.78 (m, 1H),), MS (DCI/NH₃)m/z 339 (M+H)⁺. Anal. Calculated for C₁₇H₂₉N₃O₂S: C, 60.14; H, 8.61; N,12.38. Found C, 60.22; H, 8.71; N, 12.35.

Example 181N-[(2Z)-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-N′-[(1S)-1,2,2-trimethylpropyl]urea

The product of Example 178A and (1S)-1,2,2-trimethylpropylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (s, 9H) 0.99 (d, J=7 Hz,3H) 1.14-1.26 (m, J=11 Hz, 1H) 1.36-1.49 (m, 3H) 1.52-1.59 (m, 1H)1.74-1.82 (m, 1H) 3.20-3.28 (m, 1H) 3.52-3.70 (m, 2H) 3.78-4.08 (m, 3H)6.46-6.60 (m, 2H) 7.10 (t, J=5 Hz, 1H), MS (DCI/NH₃) m/z 326 (M+H)⁺.Anal. Calculated for C₁₆H₂₇N₃O₂S: C, 59.04; H, 8.36; N, 12.91. Found C,59.08; H, 8.28; N, 12.80.

Example 182N-[(2Z)-5-methyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-N′-[(1S)-1,2,2-trimethylpropyl]urea

The product of Example 157A and (1S)-1,2,2-trimethylpropylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (s, 9H) 0.98 (d, J=7 Hz,3H) 1.11-1.30 (m, 1H) 1.45 (s, 3H) 1.51 (d, 2H) 2.12 (s, 4H) 3.21-3.30(m, 1H) 3.48-3.70 (m, 2H) 3.78-4.05 (m, 3H) 6.46 (dd, J=9, 3 Hz, 1H)6.80 (dd, J=5, 2 Hz, 1H), MS (DCI/NH₃) m/z 339 (M+H)⁺. Anal. Calculatedfor C₁₇H₂₉N₃O₂S: C, 60.14; H, 8.61; N, 12.38. Found C, 60.10; H, 8.81;N, 12.02.

Example 1831-(4-Methylcyclohexyl)-3-[(2Z)-4,5-dimethyl-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 176A and 4-methylcyclohexylamine were processedusing the method described in Example 169A to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.82-1.02 (m, 4H) 1.15-1.29 (m, 3H)1.38-1.51 (m, 4H) 1.52-1.70 (m, 4H) 1.78 (s, 3H) 2.06 (s, 3H) 2.11 (s,3H) 3.19-3.28 (m, 1H) 3.61 (s, 1H) 3.69-3.86 (m, 3H) 3.98 (dd, J=14, 3Hz, 1H) 6.57 (d, J=8 Hz, 1H), MS (DCI/NH₃) m/z 366 (M+H)⁺. Anal.Calculated for C₁₈H₂₃N₃O₂S: C, 62.45; H, 8.55; N, 11.50. Found C, 62.77;H, 8.86; N, 1150.

Example 1841-(2,2-Dimethylpropyl)-3-[(2Z)-5-methyl-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 157A and 2,2-dimethylpropylamine were processedusing the method described in Example 169A to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.81 (s, 9H) 1.09-1.26 (m, 1H) 1.34-1.59(m, 4H) 1.69-1.87 (m, 1H) 2.12 (d, J=1 Hz, 3H) 2.80-2.98 (m, 2H)3.08-3.27 (m, 1H) 3.52-3.67 (m, 1H) 3.80-4.06 (m, 3H) 6.68-6.76 (m, 1H)6.78-6.90 (m, 1H), MS (DCI/NH₃) m/z 326 (M+H)⁺. Anal. Calculated forC₁₆H₂₇N₃O₂S: C, 59.04; H, 8.36; N, 12.91. Found C, 58.89; H, 8.56; N,12.71.

Example 1851-tert-Butyl-3-[(2Z)-4,5-dimethyl-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 176A and tert-butylamine were processed using themethod described in Example 169A to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.13-1.22 (m, 1H) 1.27 (s, 9H) 1.44 (d, J=4 Hz,3H) 1.60 (d, J=12 Hz, 1H) 1.77 (s, 1H) 2.06 (s, 3H) 2.11 (s, 3H)3.16-3.28 (m, 1H) 3.55-3.68 (m, 1H) 3.68-3.87 (m, 2H) 4.00 (dd, J=14, 3Hz, 1H) 6.90 (d, J=9 Hz, 1H), MS (DCI/NH₃) m/z 326 (M+H)⁺. Anal.Calculated for C₁₆H₂₇N₃O₂S.0.3H₂O: C, 58.02; H, 8.41; N, 12.70. Found C,58.44; H, 8.12; N, 12.41.

Example 1861-(1,1-Dimethylpropyl)-3-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]ureaExample 186A4,5-Dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylideneaminehydrobromide

A mixture of 2-amino-4,5-dimethylthiazole and2-(bromomethyl)tetrahydrofuran were processed using the method describedin Example 12A to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.43-1.64 (m, 1H) 1.73-2.00 (m, 3H) 2.17 (s, 3H) 2.19 (s, 3H)3.53-3.68 (m, 1H) 3.71-3.85 (m, 1H) 3.91-4.17 (m, 3H) 9.34 (s, 1H),), MS(DCI/NH₃) m/z 212 (M+H)⁺.

Example 186B1-(1,1-Dimethylpropyl)-3-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 186A and 1,1-dimethylpropylamine were processedusing the method described in Example 169A to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (t, J=7 Hz, 3H) 1.22-1.31 (m, 6H)1.53-1.72 (m, 3H) 1.75-1.86 (m, 1H) 1.91-2.05 (m, 1H) 2.08-2.20 (m, 1H)2.24 (s, 6H) 3.55-3.71 (m, 1H) 3.76-3.88 (m, 1H) 4.09-4.20 (m, 1H) 4.30(s, 1H) 4.40-4.54 (m, 1H) 6.94 (d, J=9 Hz, 1H), MS (DCI/NH₃) m/z 326(M+H)⁺.

Example 1871-(2,2-Dimethylpropyl)-3-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 186A and 2,2-dimethylpropylamine were processedusing the method described in Example 169A to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.86 (s, 9H) 1.54-1.65 (m, 1H) 1.77-1.97(m, 3H) 2.07 (s, 3H) 2.10-2.14 (m, 3H) 2.78-2.97 (m, 2H) 3.54-3.65 (m,1H) 3.71-3.85 (m, 2H) 3.98-4.11 (m, 1H) 4.14-4.31 (m, 1H) 6.66 (t, J=7Hz, 1H), MS (DCI/NH₃) m/z 326 (M+H)⁺. Anal. Calculated for C₁₆H₂₇N₃O₂S:C, 59.04; H, 8.36; N, 12.91. Found C, 58.91; H, 8.64; N, 12.77.

Example 1881-[(2Z)-4,5-Dimethyl-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-3-(3,3,5,5-tetramethylcyclohexyl)urea

The product of Example 176A and 3,3,5,5-tetramethylcyclohexylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.88 (s, 6H) 0.91-1.01 (m, 2H)1.01-1.05 (m, 6H) 1.20 (d, J=14 Hz, 2H) 1.37-1.62 (m, 7H) 1.77 (d, J=4Hz, 1H) 2.04-2.09 (m, 3H) 2.09-2.15 (m, 3H) 3.09-3.28 (m, 1H) 3.55-3.87(m, 4H) 3.98 (dd, J=14, 3 Hz, 1H) 6.56 (d, J=8 Hz, 1H), MS (DCI/NH₃) m/z408 (M+H)⁺. Anal. Calculated for C₂₂H₃₇N₃O₂S.0.4H₂O: C, 63.7; H, 89.18N,10.13. Found C, 63.49; H, 8.93; N, 10.12.

Example 189N-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-N′-[(1S)-1,2,2-trimethylpropyl]urea

The product of Example 186A and (1S)-1,2,2-trimethylpropylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.83 (s, 9H) 0.98 (dd, J=7, 2Hz, 3H) 1.53-1.64 (m, 1H) 1.76-1.99 (m, 3H) 2.06 (s, 3H) 2.11 (s, 3H)3.53-3.65 (m, 2H) 3.73-3.84 (m, 2H) 4.05-4.14 (m, 1H) 4.17-4.22 (m, 1H)6.34-6.42 (m, 1H), MS (DCI/NH₃) m/z 339 (M+H)⁺. Anal. Calculated forC₁₇H₂₉N₃O₂S: C, 60.14; H, 8.61 N, 12.38. Found C, 60.06; H, 8.95; N,12.29.

Example 190N-[(2Z)-4,5-dimethyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-N′-[(1R)-1,2,2-trimethylpropyl]urea

The product of Example 176A and (1R)-1,2,2-trimethylpropylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (s, 9H) 0.99 (dd, J=7, 5Hz, 3H) 1.13-1.30 (m, 1H) 1.38-1.50 (m, 3H) 1.54-1.68 (m, J=11 Hz, 1H)1.74-1.85 (m, 1H) 2.06 (s, 3H) 2.11 (s, 3H) 3.19-3.27 (m, 1H) 3.53-3.66(m, 1H) 3.71-3.88 (m, 3H) 3.95-4.12 (m, 1H) 6.37 (d, J=9 Hz, 1H), MS(DCI/NH₃) m/z 354 (M+H)⁺. Anal. Calculated for C₁₈H₃₁N₃O₂S: C, 61.15; H,9.04; N, 11.89. Found C, 61.36; H, 9.08; N, 11.80.

Example 1911-tert-Butyl-3-[(2Z)-5-methyl-3-(tetrahydropyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 157A and tent-butyl amine were processed usingthe method described in Example 169A to afford the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.11-1.22 (m, 1H) 1.27 (s, 9H) 1.42-1.47(m, J=1 Hz, 3H) 1.47-1.60 (m, 1H) 1.78 (d, J=5 Hz, 1H) 2.12 (s, 3H)3.17-3.26 (m, 1H) 3.55-3.66 (m, J=6 Hz, 1H) 3.80-3.95 (m, 3H) 6.34 (s,1H) 6.79 (s, 1H), MS (DCI/NH₃) m/z 326 (M+H)⁺. Anal. Calculated forC₁₆H₂₇N₃O₂S.0.3H₂O: C, 58.08; H, 8.41; N, 12.70. Found C, 58.44; H,8.12; N, 12.41.

Example 1921-(2,3-Dichlorophenyl)-3-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 186A and 2,3-dichlorophenylamine were processedusing the method described in Example 169A to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.50-1.67 (m, 1H) 1.75-2.06 (m, 3H) 2.15(s, 3H) 2.18 (s, 3H) 3.57-3.69 (m, 1H) 3.72-3.83 (m, 1H) 3.83-3.96 (m,1H) 4.10-4.30 (m, 2H) 7.30 (s, 1H) 7.32 (d, J=1 Hz, 1H) 7.97-8.03 (m,1H) 8.22 (s, 1H), MS (DCI/NH₃) m/z 400, 401 (M+H)⁺. Anal. Calculated forC₁₃H₂₃Cl₃N₃O₂S.0.3MeOH: C, 54.15; H, 8.23; N, 14.20. Found C, 54.47; H,7.91N, 13.99.

Example 1931-(2,2-Dimethylpropyl)-3-[(2Z)-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 5A and 2,2-dimethylpropylamine were processedusing the method described in Example 169A to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.77 (t, J=7 Hz, 3H) 1.21 (s, 6H) 1.66(q, J=7 Hz, 2H) 2.21 (s, 3H) 3.23 (s, 3H) 3.57 (t, J=5 Hz, 2H) 4.07 (t,J=5 Hz, 2H) 6.21 (s, 1H) 8.10 (d, J=9 Hz, 1H),), MS (DCI/NH₃) m/z 286(M+H)⁺. Anal. Calculated for C₁₃H₂₃N₃O₂S.0.1MeOH: C, 54.70; H, 8.15; N,14.26. Found C, 54.47; H, 7.91; N, 13.99.

Example 194N-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-N′-[(1R)-1,2,2-trimethylpropyl]urea

The product of Example 186A and (1R)-1,2,2-trimethylpropylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (s, 9H) 0.98 (dd, J=7, 2Hz, 3H) 1.49-1.66 (m, 1H) 1.74-1.99 (m, 3H) 2.06 (s, 3H) 2.11 (s, 3H)3.52-3.67 (m, 2H) 3.72-3.88 (m, 2H) 4.10 (dt, J=14, 4 Hz, 1H) 4.16-4.27(m, 1H) 6.37 (dd, J=10, 4 Hz, 1H), m/z 339 (M+H)⁺. Anal. Calculated forC₁₇H₂₉N₃O₂S: C, 60.14; H, 8.61; N, 12.38. Found C, 60.18; H, 8.88; N,12.33.

Example 195N-[(1S)-1,2-dimethylpropyl]-N′-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 186A and (1S)-1,2,2-trimethylpropylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.83 (s, 9H) 0.98 (dd, J=7, 2Hz, 3H) 1.52-1.66 (m, 1H) 1.75-1.97 (m, 3H) 2.06 (s, 3H) 2.11 (s, 3H)3.51-3.66 (m, 2H) 3.72-3.86 (m, 2H) 4.10 (dt, J=14, 4 Hz, 1H) 4.19 (s,1H) 6.37 (dd, J=10, 4 Hz, 1H), m/z 339 (M+H)⁺. Anal. Calculated forC₁₇H₂₉N₃O₂S: C, 60.14; H, 8.61; N, 12.38. Found C, 60.06; H, 8.95; N,12.29.

Example 1961-(1-Cyclopropylethyl)-3-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]urea

The product of Example 12A and 1-cyclopropylethylamine were processedusing the method described in Example 169A to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.05-0.15 (m, 1H) 0.18-0.55 (m, 3H)0.78-0.92 (m, 1H) 1.11 (dd, J=7, 2 Hz, 3H) 1.51-1.64 (m, 1H) 1.75-1.99(m, 3H) 2.07 (s, 3H) 2.12 (s, 3H) 3.06-3.22 (m, 1H) 3.61 (dd, 1H)3.73-3.85 (m, 2H) 4.02-4.14 (m, 1H) 4.15-4.25 (m, 1H) 6.57-6.70 (m, 1H);m/z 324 (M+H)⁺. Anal. Calculated for C₁₆H₂₅N₃O₂S: C, 59.41; H, 7.79; N,12.99. Found C, 59.13; H, 7.78; N, 12.88.

Example 1971-[(2Z)-5-(2,4-Difluorophenyl)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-3-(1,1-dimethylpropyl)ureaExample 197AN-[5-chloro-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]acetamide

A flask was charged with 2-acetamido-5-chlorothiazole (Lancaster, 19.3g, 110 mmol) in 200 mL of 2:1 THF/DMF. To the solution was added sodiumhydride (60% dispersion in mineral oil, 5.44 g, 142 mmol). The mixturewas stirred at room temperature for 15 min and then 2-bromoethyl methylether (18.3 g, 131 mmol) was added. The reaction mixture was warmed to85° C. and stirred overnight. After cooling to room temperature, themixture was diluted with ethyl acetate and washed with water. Theorganic extract was dried (MgSO₄), filtered, and concentrated. Theresidue was purified by flash chromatography on SiO₂ using a gradient of0% to 100% ethyl acetate:hexane to provide 10.3 g (42%) of the titlecompound as the more polar regioisomer: ¹H NMR (300 MHz, CDCl₃) δ 2.28(s, 3H) 3.35 (s, 3H) 3.65-3.71 (m, 2H) 4.28-4.36 (m, 2H) 7.00 (s, 1H);MS (ESI⁺) m/z 235 (M+H)⁺.

Example 197BN-[5-(2,4-difluorophenyl)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]acetamide

A flask was charged with the product from Example 197A (10.2 g, 42.6mmol), 2,6-difluorophenylboronic acid (8.08 g, 51.1 mmol), Na₂CO₃ (64.0mL of a 2 M aqueous solution, 128 mmol) and PdCl₂(PPh₃)₂ (1.5 g, 2.13mmol) in 100 mL of DME/H₂O/ethanol (7:3:2). The mixture was warmed to85° C. and stirred overnight. After cooling to room temperature, themixture was diluted with ethyl acetate and washed with water. Theorganic extract was dried (MgSO₄), filtered, and concentrated. Theresidue was purified by flash chromatography on SiO₂ using a gradient of0% to 100% ethyl acetate: hexane to provide 11.5 g (86%) of the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ 2.17 (s, 3H) 3.27 (s, 3H) 3.71 (t,J=5.3 Hz, 2H) 4.37 (t, J=5.4 Hz, 2H) 7.17-7.24 (m, 1H) 7.38-7.48 (m, 1H)7.64-7.74 (m, 1H) 7.88 (s, 1H); MS (ES I⁺) m/z 313 (M+H)⁺.

Example 197CN-5-(2,4-difluoro-phenyl)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylideneamine

To a solution of the product from Example 197B (11.5 g, 36.8 mmol) in100 mL of THF was added 25 mL of 5 N aqueous HCl. The mixture was warmedto 40° C. and stirred overnight. After cooling to room temperature, thesolvent was removed under reduced pressure and the residue diluted withethyl acetate. The mixture was neutralized to pH 7 with saturatedaqueous NaHCO₃ and then washed with water. The organic extract was dried(MgSO₄), filtered and concentrated. The residue was purified by flashchromatography on SiO₂ using a gradient of 0% to 100% ethylacetate:hexane to provide 8.5 g (85%) of the title compound: ¹H NMR (300MHz, DMSO-d₆) δ 3.27 (s, 3H) 3.57 (t, J=5.3 Hz, 2H) 3.86 (t, J=5.4 Hz,2H) 7.06-7.14 (m, Hz, 1H) 7.25 (s, 1H) 7.29 (dd, J=9.2, 2.7 Hz, 2H) 7.34(dd, J=5.9, 3.2 Hz, 1H) 7.94 (s, 1H); MS (ES I⁺) m/z 271 (M+H)⁺.

Example 197D1-[(2Z)-5-(2,4-Difluorophenyl)-3-(2-methoxyethyl)-1,3-thiazol-2-ylidene]-3-(1,1-dimethylpropyl)urea

A mixture of the product of Example 197C and 1,1-dimethylpropylaminewere processed using the method described in Example 169A to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78 (t, J=7.06 Hz, 3H)1.24 (s, 6H) 1.68 (q, J=7.67 Hz, 2H) 3.27 (s, 3H) 3.66 (t, J=5.52 Hz,2H) 4.20 (t, J=5.22 Hz, 2H) 6.49 (m, 1H) 7.16 (td, J=7.98, 1.84 Hz, 1H)7.38 (m, 1H) 7.58 (m, 1H) 7.61 (s, 1H); MS (DCI/NH₃) m/z 384 (M+H)⁺.

Example 1981-[(2Z)-5-(2,4-Difluorophenyl)-3-(2-methoxyethyl)-1,3-thiazol-2-ylidene]-(1-methylpropyl)urea

A mixture of the product of Example 197C and sec-butylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) ppm 0.84 (t, J=7.32 Hz, 3H) 1.05 (d,J=6.41 Hz, 3H) 1.42 (m, 2H) 3.27 (s, 3H) 3.59 (m, 1H) 3.66 (t, J=5.49Hz, 2H) 4.21 (t, J=5.80 Hz, 2H) 6.93 (d, J=8.54 Hz, 1H) 7.18 (td,J=8.24, 2.44 Hz, 1H) 7.39 (m, 1H) 7.57 (td, J=8.85, 6.41 Hz, 1H) 7.62(brs, 1H); MS (DCI/NH₃) m/z 370 (M+H)⁺.

Example 1991-Cyclopentyl-3-[(2Z)-5-(2,4-difluorophenyl)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]urea

A mixture of the product of Example 197C and cyclopentylamine wereprocessed using the method described in Example 169A to afford the titlecompound. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.47 (m, 4H) 1.65 (m, 2H) 1.80(m, 2H) 3.27 (s, 3H) 3.66 (t, J=5.49 Hz, 2H) 3.95 (m, 1H) 4.20 (t,J=5.19 Hz, 2H) 7.10 (d, J=7.63 Hz, 1H) 7.18 (td, J=8.24, 2.44 Hz, 1H)7.39 (m, 1H) 7.57 (m, 1H) 7.63 (s, 1H); MS (DCI/NH₃) m/z 382 (M+H)⁺.

Example 2001-[(2Z)-5-(2,4-Difluorophenyl)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-3-(4-methylcyclohexyl)urea

A mixture of the product of Example 197C and 4-methylcyclohexylaminewere processed using the method described in Example 169A to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.90 (m, 3H) 0.98 (m,2H) 1.49 (m, 8H) 3.27 (s, 3H) 3.66 (m, 2H) 4.21 (m, 2H) 6.93 (t, J=8.90Hz, 1H) 7.17 (td, J=7.06, 2.45 Hz, 1H) 7.38 (m, 1H) 7.56 (m, 1H) 7.62(m, 1H); MS (DCI/NH₃) m/z 410 (M+H)⁺.

Example 202N-[(2Z)-5-tert-butyl-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-2-ethoxybenzamideExample 202A 5-tert-butylthiazol-2-amine

To a flask equipped with a Dean-Stark trap was added 3,3-dimethylbutanal(Aldrich, 5.0 g, 50 mmol), pyrrolidine (Aldrich, 4.4 mL, 52 mmol) andp-toluenesulfonic acid monohydrate (10 mg) in cyclohexane (70 mL). Themixture was heated to reflux for 3 hours, the water was removed and theorganic phase was concentrated under reduced pressure. The residue wasdissolved in methanol (20 mL) and cooled to 0° C. Sulfur (Aldrich, 1.6g, 50 mmol) and a solution of cyanamide (Aldrich, 2.1 g, 50 mmol) inmethanol (5 mL) were added. The reaction mixture was allowed to warm toambient temperature, stirred for 12 hours, and was concentrated underreduced pressure. The residue was purified by column chromatography(SiO₂, 2% methanol in CH₂Cl₂) to afford the title compound. MS (ESI⁺)m/z 157 (M+H)⁺.

Example 202B 5-tert-butyl-3-(2-methoxyethyl)thiazol-2(3H)-iminehydrobromide

A mixture of Example 202A and commercially available 2-bromoethyl methylether (Aldrich) were processed according to the method described inExample 12A to afford the title compound. MS (ESI⁺) m/z 215 (M+H)⁺.

Example 202CN-[(2Z)-5-tert-butyl-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-2-ethoxybenzamide

Commercially available 2-ethoxybenzoic acid (Aldrich) and Example 202Bwere processed using the method described in Example 58 to afford thetitle compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.28-1.36(m, 12H), 3.26 (s, 3H), 3.71 (t, J=5.4 Hz, 2), 4.06 (q, J=6.9 Hz, 2H),4.31 (t, J=5.4 Hz, 2H), 6.95 (td, J=7.4, 0.8 Hz, 1H), 7.05 (dd, J=8.5,0.7 Hz, 1H), 7.21 (s, 1H), 7.32-7.42 (m, 1H), 7.67 (dd, J=7.6, 1.9 Hz,1H)); MS (ESI⁺) m/z 363 (M+H)⁺.

Example 2032-ethoxy-N-[(2Z)-5-methyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 203A (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate

To a solution of tetrahydro-2H-pyran-4-ylmethanol (Combi-Blocks, 2.0 g,17.2 mmol) in 10 mL of of CH₂Cl₂ and 10 mL of of pyridine was addedp-toluenesulfonyl chloride (3.5 g, 18.1 mmol) in portions over 15minutes. The mixture stirred at ambient temperature for 16 hours and wasquenched with 10 mL of saturated, aqueous NaHCO₃. The layers wereseparated and the aqueous layer was extracted with three 10 mL portionsof CH₂Cl₂. The combined organic extracts were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to afford thetitle compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.05-1.25(m, 2H), 1.40-1.53 (m, 2H), 1.73-1.94 (m, 1H), 2.43 (s, 3H), 3.14-3.28(m, 2H), 3.71-3.84 (m, 2H), 3.88 (d, J=6.4 Hz, 2H), 7.48 (d, J=8.5 Hz,2H), 7.79 (d, J=8.5 Hz, 2H); MS (DCI/NH₃) m/z 288 (M+NH₄)⁺.

Example 203B5-methyl-3-((tetrahydro-2H-pyran-4-yl)methyl)thiazol-2(3H)-imine

A mixture of Example 203A (1.9 g, 7.0 mmol), 2-amino-5-methylthiazole(0.80 g, 7.0 mmol) and tetrabutylammonium iodide (1.3 g, 3.5 mmol) in 3mL of N,N-dimethylformamide was warmed to 85° C. and was allowed to stirfor 24 hours. The mixture was diluted with 10 mL of CH₂Cl₂, washed with10% aqueous NaHCO₃, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification via columnchromatography (SiO₂, 10% methanol in ethyl acetate then 9:1:0.1CH₂Cl₂:methanol:NH₄OH) afforded the title compound. MS (DCI/NH₃) m/z 213(M+H)⁺.

Example 203C2-ethoxy-N-[(2Z)-5-methyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of Example 203B (0.11 g, 0.52 mmol) in 10 mL oftetrahydrofuran and 1 mL of N,N-dimethylformamide at ambient temperaturewas added triethylamine (0.22 mL, 1.6 mmol) followed by 2-ethoxybenzoylchloride (0.11 g, 0.57 mmol). This mixture was warmed to 50° C., stirredfor 3 hours, was quenched with 10 mL of saturated aqueous NH₄Cl, anddiluted with 10 mL of CH₂Cl₂. The layers were separated and the aqueouslayer was extracted with three 5 mL portions of CH₂Cl₂. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification via flash columnchromatography (SiO₂, 50% hexanes in ethyl acetate) afforded the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.46 (t, J=7.0 Hz, 3H),1.52-1.61 (m, 1H), 1.57 (s, 3H), 2.14-2.26 (m, 1H), 2.29 (d, J=1.4 Hz,3H), 3.36 (dt, J=11.7, 2.4 Hz, 2H), 3.98 (ddd, J=11.4, 4.1, 1.5 Hz, 2H),4.06 (d, J=7.5 Hz, 2H), 4.17 (q, J=6.8 Hz, 2H), 6.59-6.62 (m, 1H),6.93-7.01 (m, 2H), 7.36 (ddd, J=8.3, 7.5, 1.9 Hz, 1H), 7.97 (dd, J=8.0,1.9 Hz, 1H); MS (DCI/NH₃) m/z 361 (M+H)⁺. Anal. Calculated forC₁₉H₂₄N₂O₃S: C, 63.31; H, 6.71; N, 7.77. Found: C, 63.27; H, 6.57; N,7.48.

Example 2042,4-dimethoxy-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 204A5-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-imine

A mixture of 2-amino-5-methylthiazole (1 g, 8.7 mmol) and2-(bromomethyl)tetrahydrofuran (1.1 mL, 10 mmol) was warmed to 85° C.and was allowed to stir for 24 hours. The mixture was cooled to ambienttemperature and purified via flash column chromatography (SiO₂, 10%methanol in ethyl acetate then 9:1:0.1 CH₂Cl₂:methanol:NH₄OH) to affordthe title compound. MS (DCI/NH₃) m/z 199 (M+H)⁺.

Example 204B 2,4-dimethoxybenzoyl chloride

A solution of 2,4-dimethoxybenzoic acid (0.25 g, 1.4 mmol) in 5 mL ofSOCl₂ was warmed to reflux and was allowed to stir for 2 hours. Themixture was cooled to ambient temperature and concentrated under reducedpressure. The crude material was diluted with 5 mL of toluene andconcentrated under reduced pressure. This dilution with toluene andconcentration was repeated two additional times to give the crude titlecompound which was used without additional purification orcharacterization.

Example 204C2,4-dimethoxy-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of Example 204A (0.18 g, 0.91 mmol) in 10 mL oftetrahydrofuran at ambient temperature was added triethylamine (0.38 mL,2.7 mmol) followed by Example 204B (1.4 mmol) in 3 mL of tetrahydrofuranvia cannula. This mixture was warmed to 50° C., stirred for 3 hours,then quenched with 10 mL of saturated aqueous NH₄Cl, and diluted with 10mL of CH₂Cl₂. The layers were separated and the aqueous phase wasextracted three 5 mL portions of CH₂Cl₂. The combined organic extractswere dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. Purification via column chromatography (SiO₂, 50%hexanes in ethyl acetate) afforded the title compound. ¹H NMR (300 MHz,CD₃OD) δ ppm 1.65-1.79 (m, 1H), 1.84-1.96 (m, 2H), 1.99-2.15 (m, 1H),2.31 (d, J=1.4 Hz, 3H), 3.71-3.81 (m, 1H), 3.84-3.93 (m, 1H), 3.85 (s,3H), 3.86 (s, 3H), 4.19-4.42 (m, 3H), 6.51-6.62 (m, 2H), 7.05-7.10 (m,1H), 8.03 (d, J=8.8 Hz, 1H); MS (DCI/NH₃) m/z 363 (M+H)⁺. Anal.Calculated for C₁₈H₂₂N₂O₄S: C, 59.65; H, 6.12; N, 7.73. Found: C, 59.47;H, 6.01; N, 7.62.

Example 2055-chloro-2-methoxy-N-[(2Z)-4-methyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 205A4-methyl-3-((tetrahydro-2H-pyran-2-yl)methyl)thiazol-2(3H)-imine

A mixture of 2-amino-4-methylthiazole (1.0 g, 8.8 mmol) and2-(bromomethyl)tetrahydropyran (1.1 mL, 8.8 mmol) was warmed to 85° C.and was allowed to stir for 24 hours. The mixture was cooled to ambienttemperature and the crude material was purified via columnchromatography (SiO₂, 10% methanol in ethyl acetate then 9:1:0.1CH₂Cl₂:methanol:NH₄OH) to afford the title compound. MS (DCI/NH₃) m/z213 (M+H)⁺.

Example 205B 5-chloro-2-methoxybenzoyl chloride

A solution of 2-methoxy-5-chlorobenzoic acid (0.37 g, 2.0 mmol) in 10 mLof SOCl₂ was warmed to reflux and was allowed to stir for 2 hours. Themixture was cooled to ambient temperature and concentrated under reducedpressure. The crude material was diluted with 5 mL of toluene andconcentrated under reduced pressure. This dilution with toluene andconcentration was repeated two additional times to afford the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 3.82 (s, 3H),7.16 (d, J=8.8 Hz, 1H), 7.49-7.59 (m, 1H), 7.61 (d, J=2.7 Hz, 1H).

Example 205C5-chloro-2-methoxy-N-[(2Z)-4-methyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of Example 205A (0.21 g, 1.0 mmol) in 10 mL oftetrahydrofuran at ambient temperature was added triethylamine (0.41 mL,3.0 mmol) followed by Example 205B (2.0 mmol) in 5 mL of tetrahydrofuranvia cannula. This mixture was warmed to 50° C., stirred for 2 hours,then quenched with 10 mL of saturated aqueous NH₄Cl, and diluted with 10mL of CH₂Cl₂. The layers were separated and the aqueous phase wasextracted with three 5 mL portions of CH₂Cl₂. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. Purification via column chromatography (SiO₂,50% hexanes in ethyl acetate) afforded the title compound. ¹H NMR (300MHz, CD₃OD) δ ppm 1.31-1.48 (m, 1H), 1.47-1.67 (m, 3H), 1.70-1.82 (m,1H), 1.84-1.98 (m, 1H), 2.40 (d, J=1.0 Hz, 3H), 3.26-3.40 (m, 1H),3.82-3.94 (m, 2H), 3.87 (s, 3H), 4.00-4.11 (m, 1H), 4.42 (dd, J=13.9,2.7 Hz, 1H), 6.55 (d, J=1.0 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 7.40 (dd,J=8.8, 2.7 Hz, 1H), 7.87 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 381 (M+H)⁺.Anal. Calculated for C₁₈H₂₁ClN₂O₃S: C, 56.76; H, 5.56; N, 7.35. Found:C, 56.58; H, 5.43; N, 7.19.

Example 2065-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

To Example 203B (0.11 g, 0.52 mmol) and triethylamine (0.22 mL, 1.6mmol) in 10 mL of tetrahydrofuran and 1 mL of N,N-dimethylformamide wasadded Example 205B (0.68 mmol) in 2 mL of tetrahydrofuran. This mixturewas warmed to 50° C., stirred for 2 hours, then quenched with 10 mL ofsaturated aqueous NH₄Cl, and diluted with 10 mL of CH₂Cl₂. The layerswere separated and the aqueous phase was extracted with three 5 mLportions of CH₂Cl₂. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification via flash column chromatography (SiO₂, 50% hexanes in ethylacetate) resulted in the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm1.34-1.60 (m, 4H), 2.18-2.32 (m, 1H), 2.34 (d, J=1.4 Hz, 3H), 3.38 (dt,J=11.6, 2.5 Hz, 2H), 3.86 (s, 3H), 3.94 (ddd, J=11.6, 4.2, 1.9 Hz, 2H),4.14 (d, J=7.5 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H), 7.12 (q, J=1.4 Hz, 1H),7.40 (dd, J=8.8, 2.7 Hz, 1H), 7.83 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z381 (M+H)⁺. Anal. Calculated for C₁₈H₂₁ClN₂O₃S: C, 56.76; H, 5.56; N,7.35. Found: C, 56.48; H, 5.46; N, 7.23.

Example 2075-chloro-2-methoxy-N-[(2Z)-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 207A 3-((tetrahydro-2H-pyran-2-yl)methyl)thiazol-2(3H)-imine

A mixture of 2-aminothiazole (1.0 g, 10 mmol) and2-(bromomethyl)tetrahydro-2H-pyran (1.3 mL, 10 mmol) was warmed to 85°C. and was allowed to stir for 24 hours. The mixture was cooled toambient temperature and the crude material was purified via columnchromatography (SiO₂, 10% methanol in ethyl acetate then 9:1:0.1CH₂Cl₂:methanol:NH₄OH) to afford the title compound. MS (DCI/NH₃) m/z199 (M+H)⁺.

Example 207B5-chloro-2-methoxy-N-[(2Z)-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of Example 207A (0.19 g, 0.96 mmol) in 10 mL oftetrahydrofuran at ambient temperature was added triethylamine (0.40 mL,2.9 mmol) followed by Example 205B (2.0 mmol) in 5 mL of tetrahydrofuranvia cannula. This mixture was warmed to 50° C., stirred for 2 hours,then quenched with 10 mL of saturated aqueous NH₄Cl, and diluted with 10mL of CH₂Cl₂. The layers were separated and the aqueous phase wasextracted with three 5 mL portions of CH₂Cl₂. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. Purification via column chromatography (SiO₂,50% hexanes in ethyl acetate) afforded the title compound. ¹H NMR (300MHz, CD₃OD) δ ppm 1.20-1.41 (m, 1H), 1.46-1.63 (m, 3H), 1.67-1.77 (m,1H), 1.82-1.96 (m, 1H), 3.35-3.45 (m, 1H), 3.75-3.85 (m, 1H), 3.86 (s,3H), 3.89-4.00 (m, 1H), 4.19-4.27 (m, 1H), 4.38-4.46 (m, 1H), 6.91 (d,J=4.7 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 7.38 (d, J=4.7 Hz, 1H), 7.41 (dd,J=8.8, 3.1 Hz, 1H), 7.85 (d, J=3.1 Hz, 1H); MS (DCI/NH₃) m/z 367 (M+H)⁺.Anal. Calculated for C₁₇H₁₉ClN₂O₃S: C, 55.66; H, 5.22; N, 7.64. Found:C, 55.72; H, 5.08; N, 7.55.

Example 2085-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 208A (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (R)-tetrahydrofurfuryl alcohol (Lancaster, 1.0 g, 9.8mmol) in 5 mL of CH₂Cl₂ and 5 mL of pyridine was added p-toluenesulfonylchloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture wasstirred at ambient temperature for 3 hours and was quenched with 10 mLof saturated, aqueous NaHCO₃. The layers were separated and the aqueouslayer was extracted with three 5 mL portions of CH₂Cl₂. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound. MS(DCI/NH₃) m/z 257 (M+H)⁺, 274 (M+NH₄).

Example 208B(R)-5-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-imine

A mixture of Example 208A (1.5 g, 5.9 mmol), 2-amino-5-methylthiazole(0.68 g, 5.9 mmol) and tetrabutylammonium iodide (1.1 g, 3.0 mmol) in 3mL of N,N-dimethylformamide was warmed to 85° C. and was allowed to stirfor 48 hours. The mixture was diluted with 10 mL of CH₂Cl₂ and thesolution was quenched with 10 mL of saturated, aqueous NaHCO₃. Thelayers were separated and the aqueous layer was extracted twice with 10mL portions of CH₂Cl₂. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification via column chromatography (SiO₂, 10% methanol in ethylacetate then 9:1:0.1 CH₂Cl₂:methanol:NH₄OH) afforded the title compound.MS (DCI/NH₃) m/z 199 (M+H)⁺.

Example 208C 5-chloro-2-methoxybenzoyl chloride

A solution of 2-methoxy-5-chlorobenzoic acid (0.22 g, 1.2 mmol) in 10 mLof SOCl₂ was warmed to reflux and was allowed to stir for 2 hours. Themixture was cooled to ambient temperature and concentrated under reducedpressure. The crude material was diluted with 5 mL of toluene andconcentrated under reduced pressure. This dilution with toluene andconcentration was repeated two additional times to afford the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 3.82 (s, 3H),7.16 (d, J=8.8 Hz, 1H), 7.49-7.59 (m, 1H), 7.61 (d, J=2.7 Hz, 1H).

Example 208D5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of Example 208B (0.23 g, 1.2 mmol) in 10 mL oftetrahydrofuran at ambient temperature was added triethylamine (0.49 mL,3.5 mmol) followed by Example 208C (1.2 mmol) in 5 mL of tetrahydrofuranvia cannula. This mixture was warmed to 50° C. and was allowed to stirfor 3 hours and was quenched with 10 mL of NH₄Cl and diluted with 10 mLof CH₂Cl₂. The layers were separated and the aqueous layer was extractedwith three 5 mL portions of CH₂Cl₂. The combined organic extracts weredried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. Purification via flash column chromatography (SiO₂, 1:1:1hexanes:ethyl acetate:CH₂Cl₂) afforded the title compound. ¹H NMR (300MHz, CD₃OD) δ ppm 1.64-1.79 (m, 1H), 1.84-1.96 (m, 2H), 2.00-2.14 (m,1H), 2.34 (d, J=1.4 Hz, 3H), 3.69-3.81 (m, 1H), 3.84-3.93 (m, 1H), 3.85(s, 3H), 4.20-4.43 (m, 3H), 7.07 (d, J=8.8 Hz, 1H), 7.14 (q, J=1.1 Hz,1H), 7.39 (dd, J=9.0, 2.9 Hz, 1H), 7.81 (d, J=2.7 Hz, 1H); MS (DCI/NH₃)m/z 367 (M+H)⁺. Anal. Calculated for C₁₇H₁₉ClN₂O₃S: C, 55.66; H, 5.22;N, 7.64. Found: C, 55.42; H, 5.08; N, 7.58.

Example 2095-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(2S)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 209A (S)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (S)-tetrahydrofurfuryl alcohol (Codexis, 1.6 g, 15.2mmol) in 5 mL of CH₂Cl₂ and 5 mL of pyridine was added p-toluenesulfonylchloride (4.3 g, 22.8 mmol) in portions over 15 minutes. The mixturestirred at ambient temperature for 3 hours and was quenched with 10 mLof saturated, aqueous NaHCO₃. The layers were separated and the aqueouslayer was extracted with three 5 mL portions of CH₂Cl₂. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound. MS(DCI/NH₃) m/z 257 (M+H)⁺, 274 (M+NH₄).

Example 209B(S)-5-methyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-imine

A mixture of Example 209A (1.6 g, 6.1 mmol), 2-amino-5-methylthiazole(0.7 g, 6.1 mmol) and tetrabutylammonium iodide (2.3 g, 6.1 mmol) in 5mL of N,N-dimethylformamide was warmed to 85° C. and was allowed to stirfor 18 hours. The mixture was diluted with 10 mL of CH₂Cl₂, washed with10% aqueous NaHCO₃, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification via columnchromatography (SiO₂, 10% methanol in ethyl acetate then 9:1:0.1CH₂Cl₂:methanol:NH₄OH) afforded the title compound. MS (DCI/NH₃) m/z 199(M+H)⁺.

Example 209C5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(2S)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamide

Example 209B (0.32 g, 1.6 mmol), triethylamine (0.67 mL, 4.8 mmol) andExample 205B (1.9 mmol) in 20 mL of tetrahydrofuran were processed as inExample 208D to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm1.64-1.79 (m, 1H), 1.84-1.96 (m, 2H), 2.00-2.13 (m, 1H), 2.34 (d, J=1.4Hz, 3H), 3.71-3.81 (m, 1H), 3.84-3.93 (m, 1H), 3.85 (s, 3H), 4.20-4.43(m, 3H), 7.07 (d, J=8.8 Hz, 1H), 7.14 (q, J=1.4 Hz, 1H), 7.39 (dd,J=9.0, 2.9 Hz, 1H), 7.81 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 367 (M+H)⁺.Anal. Calculated for C₁₇H₁₉ClN₂O₃S: C, 55.66; H, 5.22; N, 7.64. Found:C, 55.48; H, 4.96; N, 7.52.

Example 2102,2,3,3-tetrafluoro-1-methyl-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]cyclobutanecarboxamide

Example 204A (0.20 g, 1.0 mmol), triethylamine (0.42 mL, 3.0 mmol) and2,2,3,3-tetrafluoro-1-(methyl)cyclobutanecarbonyl chloride (ABCR, 0.27g, 1.3 mmol) in 15 mL of tetrahydrofuran were processed as in Example208D to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.53(s, 3H), 1.62-1.73 (m, 1H), 1.81-1.93 (m, 2H), 1.95-2.10 (m, 1H),2.27-2.44 (m, 1H), 2.32 (d, J=1.4 Hz, 3H), 3.33-3.43 (m, 1H), 3.69-3.79(m, 1H), 3.80-3.90 (m, 1H), 4.20-4.36 (m, 3H), 7.11 (dd, J=1.4, 0.7 Hz,1H); MS (DCI/NH₃) m/z 367 (M+H)⁺. Anal. Calculated for C₁₅H₁₈F₄N₂O₂S: C,49.17; H, 4.95; N, 7.65. Found: C, 49.27; H, 4.88; N, 7.58.

Example 2115-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(oxetan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 211A oxetan-2-ylmethyl 4-methylbenzenesulfonate

To a solution of 2-hydroxymethyloxetane (TCI-US, 2.0 g, 23 mmol) in 10mL of CH₂Cl₂ and 10 mL of pyridine was added p-toluenesulfonyl chloride(6.5 g, 34 mmol) in portions over 15 minutes. The mixture was stirred atambient temperature for 3 hours and was quenched with 10 mL ofsaturated, aqueous NaHCO₃. The layers were separated and the aqueouslayer was extracted with three 5 mL portions of CH₂Cl₂. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification via columnchromatography (SiO₂, 70% hexanes in ethyl acetate) afforded the titlecompound. MS (DCI/NH₃) m/z 243 (M+H)⁺, 260 (M+NH₄)⁺.

Example 211B 5-methyl-3-(oxetan-2-ylmethyl)thiazol-2(3H)-imine

A mixture of Example 211A (1.1 g, 4.6 mmol), 2-amino-5-methylthiazole(0.53 g, 4.6 mmol) and tetrabutylammonium iodide (0.85 g, 2.3 mmol) in 5mL of N,N-dimethylformamide was warmed to 85° C. and was allowed to stirfor 18 hours. The mixture was diluted with 10 mL of CH₂Cl₂, washed with10% aqueous NaHCO₃, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification via columnchromatography (SiO₂, 10% methanol in ethyl acetate then 9:1:0.1CH₂Cl₂:methanol:NH₄OH) afforded the title compound. MS (DCI/NH₃) m/z 185(M+H)⁺.

Example 211C5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(oxetan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

Example 211B (0.26 g, 1.4 mmol), triethylamine (0.59 mL, 4.2 mmol) andExample 205B (1.7 mmol) in 15 mL of tetrahydrofuran were processed as inExample 208D to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm2.35 (d, J=1.4 Hz, 3H), 2.43-2.59 (m, 1H), 2.70-2.85 (m, 1H), 3.85 (s,3H), 4.37-4.51 (m, 2H), 4.57-4.71 (m, 2H), 5.15-5.25 (m, 1H), 7.06 (d,J=9.2 Hz, 1H), 7.18 (q, J=1.1 Hz, 1H), 7.39 (dd, J=8.8, 2.7 Hz, 1H),7.79 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 353 (M+H)⁺. Anal. Calculatedfor C₁₆H₁₇ClN₂O₃S: C, 54.46; H, 4.86; N, 7.94. Found: C, 54.41; H, 4.88;N, 7.80.

Example 2125-chloro-N-[(2Z)-3-(1,3-dioxolan-2-ylmethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 212A 3-((1,3-dioxolan-2-yl)methyl)-5-methylthiazol-2(3H)-imine

A mixture of 2-amino-5-methylthiazole (1 g, 8.7 mmol) and2-bromomethyl-1,3-dioxolane (0.98 mL, 9.6 mmol) was warmed to 85° C. andwas allowed to stir for 18 hours. The mixture was cooled to ambienttemperature and purified via column chromatography (SiO₂, 10% methanolin ethyl acetate then 9:1:0.1 CH₂Cl₂:methanol:NH₄OH) to afford the titlecompound. MS (DCI/NH₃) m/z 201 (M+H)⁺.

Example 212B5-chloro-N-[(2Z)-3-(1,3-dioxolan-2-ylmethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 212A (0.25 g, 1.3 mmol), triethylamine (0.52 mL, 3.8 mmol) andExample 205B (1.5 mmol) in 15 mL of tetrahydrofuran were processed as inExample 208D to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm2.33 (d, J=1.4 Hz, 3H), 3.86 (s, 3H), 3.87-3.99 (m, 4H), 4.41 (d, J=4.1Hz, 2H), 5.27 (t, J=4.1 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 7.12 (q, J=1.4Hz, 1H), 7.40 (dd, J=8.8, 2.7 Hz, 1H), 7.87 (d, J=2.7 Hz, 1H); MS(DCI/NH₃) m/z 369 (M+H)⁺, Anal. Calculated for C₁₆H₁₇ClN₂O₄S: C, 52.10;H, 4.65; N, 7.60. Found: C, 52.15; H, 4.42; N, 7.44.

Example 2135-chloro-N-[(2Z)-3-[2-(1,3-dioxolan-2-yl)ethyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 213A 3-(2-(1,3-dioxolan-2-yl)ethyl)-5-methylthiazol-2(3H)-imine

A mixture of 2-amino-5-methylthiazole (1.0 g, 8.7 mmol) and2-(2-bromoethyl)-1,3-dioxolane (1.1 mL, 8.7 mmol) was warmed to 85° C.and was allowed to stir for 18 hours. The mixture was cooled to ambienttemperature and purified via column chromatography (SiO₂, 10% methanolin ethyl acetate then 9:1:0.1 CH₂Cl₂:methanol:NH₄OH) to afford the titlecompound. MS (DCI/NH₃) m/z 215 (M+H)⁺.

Example 213B5-chloro-N-[(2Z)-3-[2-(1,3-dioxolan-2-yl)ethyl]-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 213A (0.25 g, 1.2 mmol), triethylamine (0.49 mL, 3.5 mmol) andExample 205B (1.3 mmol) in 10 mL of tetrahydrofuran were processed as inExample 208D to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm2.18-2.25 (m, 2H), 2.33 (d, J=1.0 Hz, 3H), 3.82-3.87 (m, 2H), 3.86 (s,3H), 3.93-4.01 (m, 2H), 4.36 (dd, J=7.1 Hz, 2H), 4.93 (t, J=4.4 Hz, 1H),7.07 (d, J=8.8 Hz, 1H), 7.10 (q, J=1.4 Hz, 1H), 7.40 (dd, J=8.8, 2.7 Hz,1H), 7.96 (d, J=3.1 Hz, 1H); MS (DCI/NH₃) m/z 383 (M+H)⁺. Anal.Calculated for C₁₇H₁₉ClN₂O₄S: C, 53.33; H, 5.00; N, 7.32. Found: C,53.02; H, 4.52; N, 7.22.

Example 214N-[(2Z)-3-(1,3-dioxolan-2-ylmethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-ethoxybenzamide

Example 212A (0.20 g, 1.0 mmol), triethylamine (0.42 mL, 3.0 mmol) and2-ethoxybenzoyl chloride (0.17 g, 1.1 mmol) in 10 mL of tetrahydrofuranwere processed as in Example 208D to afford the title compound. ¹H NMR(300 MHz, CD₃OD) δ ppm 1.41 (t, J=7.0 Hz, 3H), 2.33 (d, J=1.4 Hz, 3H),3.82-4.01 (m, 4H), 4.12 (q, J=6.9 Hz, 2H), 4.40 (d, J=4.4 Hz, 2H), 5.27(t, J=4.2 Hz, 1H), 6.96 (dt, J=7.5, 0.8 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H),7.09 (q, J=1.4 Hz, 1H), 7.39 (ddd, J=8.7, 6.9, 1.7 Hz, 1H), 7.83 (dd,J=7.6, 1.9 Hz, 1H); MS (DCI/NH₃) m/z 349 (M+H)⁺. Anal. Calculated forC₁₇H₂₀N₂O₄S: C, 58.60; H, 5.79; N, 8.04. Found: C, 58.22; H, 5.32; N,7.93.

Example 2155-bromo-2-ethoxy-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 215A 5-bromo-2-ethoxybenzoic acid

To a solution of 2-ethoxybenzoic acid (3.3 g, 20.0 mmol) in 75 mL ofacetonitrile at 0° C. was added N-bromosuccinimide (3.7 g, 21 mmol) in15 mL of acetonitrile. The reaction mixture was warmed to ambienttemperature and the mixture was allowed to stir for 48 hours. Themixture was quenched with 20 mL of H₂O and the layers were separated.The aqueous layer was extracted with three 15 mL portions of CH₂Cl₂ andthe combined organic extracts were dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. Purification via columnchromatography (SiO₂, 10% hexanes in ethyl acetate) afforded the titlecompound. MS (DCI/NH₃) m/z 262, 264 (M+NH₄)⁺.

Example 215B 5-bromo-2-ethoxybenzoyl chloride

A solution of Example 215A (0.21 g, 0.86 mmol) in 5 mL of SOCl₂ waswarmed to reflux and was allowed to stir for 2 hours. The mixture wascooled to ambient temperature and concentrated under reduced pressure.The crude material was diluted with 5 mL of toluene and concentratedunder reduced pressure. This dilution with toluene and concentration wasrepeated two additional times to give the crude title compound which wasused without additional purification or characterization.

Example 215C5-bromo-2-ethoxy-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamide

Example 208B (0.17 g, 0.86 mmol), triethylamine (0.36 mL, 2.6 mmol) andExample 215B (0.86 mmol) in 10 mL of tetrahydrofuran were processed asin Example 208D to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δppm 1.39 (t, J=7.0 Hz, 3H), 1.63-1.78 (m, 1H), 1.84-1.96 (m, 2H),2.00-2.15 (m, 1H), 2.34 (d, J=1.4 Hz, 3H), 3.69-3.81 (m, 1H), 3.84-3.95(m, 1H), 4.10 (q, J=7.0 Hz, 2H), 4.19-4.43 (m, 3H), 6.99 (d, J=8.8 Hz,1H), 7.14 (q, J=1.2 Hz, 1H), 7.49 (dd, J=8.8, 2.7 Hz, 1H), 7.87 (d,J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 425, 427 (M+H)⁺. Anal. Calculated forC₁₈H₂₁BrN₂O₃S: C, 50.83; H, 4.98; N, 6.59. Found: C, 50.89; H, 4.87; N,6.51.

Example 2165-chloro-2-ethoxy-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 216A 5-chloro-2-ethoxybenzoic acid

To a solution of 2-ethoxybenzoic acid (4.4 g, 26.6 mmol) in 80 mL ofacetonitrile at 0° C. was added N-chlorosuccinimide (3.7 g, 28 mmol) in20 mL of acetonitrile dropwise over 30 minutes. The reaction mixture waswarmed to ambient temperature and the mixture was allowed to stir for 70hours. The mixture was quenched with 20 mL of H₂O and the layers wereseparated. The aqueous layer was extracted with three 15 mL portions ofCH₂Cl₂ and the combined organic extracts were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. Purificationvia recrystallization with ether and hexanes afforded the titlecompound. MS (DCI/NH₃) m/z 201 (M+H)⁺, 218 (M+NH₄)⁺.

Example 216B 5-chloro-2-ethoxybenzoyl chloride

A solution of Example 216A (0.25 g, 1.0 mmol) in 5 mL of SOCl₂ waswarmed to reflux and was allowed to stir for 2 hours. The mixture wascooled to ambient temperature and concentrated under reduced pressure.The crude material was diluted with 5 mL of toluene and concentratedunder reduced pressure. This dilution with toluene and concentration wasrepeated two additional times to give the crude title compound which wasused without additional purification or characterization.

Example 216C5-chloro-2-ethoxy-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamide

Example 208B (0.20 g, 1.0 mmol), triethylamine (0.42 mL, 3.0 mmol) andExample 216B (1.0 mmol) in 10 mL of tetrahydrofuran were processed as inExample 208D to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm1.39 (t, J=7.0 Hz, 3H), 1.62-1.77 (m, 1H), 1.83-1.97 (m, 2H), 1.99-2.14(m, 1H), 2.34 (d, J=1.4 Hz, 3H), 3.70-3.80 (m, 1H), 3.84-3.93 (m, 1H),4.10 (q, J=6.9 Hz, 2H), 4.20-4.44 (m, 3H), 7.04 (d, J=8.8 Hz, 1H), 7.14(q, J=1.4 Hz, 1H), 7.35 (dd, J=8.8, 2.7 Hz, 1H), 7.73 (d, J=2.7 Hz, 1H);MS (DCI/NH₃) m/z 381 (M+H)⁺. Anal. Calculated for C₁₈H₂₁ClN₂O₃S: C,56.76; H, 5.56; N, 7.35. Found: C, 56.36; H, 5.28; N, 7.25.

Example 2174-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 217A 4-chloro-2-methoxybenzoyl chloride

A solution of the 4-chloro-2-methoxybenzoic acid (0.24 g, 1.3 mmol) in 7mL of SOCl₂ was warmed to reflux and was allowed to stir for 2 hours.The mixture was cooled to ambient temperature and concentrated underreduced pressure. The crude material was diluted with 5 mL of tolueneand concentrated under reduced pressure. This dilution with toluene andconcentration was repeated two additional times to give the crude titlecompound which was used without additional purification orcharacterization.

Example 217B4-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

Example 204A (0.20 g, 1.0 mmol), triethylamine (0.42 mL, 3.0 mmol) andExample 217A (1.3 mmol) in 15 mL of tetrahydrofuran and 1 mL ofN,N-dimethylformamide were processed as in Example 208D to afford thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.61-1.74 (m, 1H),1.77-1.98 (m, 2H), 1.99-2.14 (m, 1H), 2.30 (d, J=1.4 Hz, 3H), 3.72-3.82(m, 1H), 3.82-3.90 (m, 1H), 3.91 (s, 3H), 4.11-4.20 (m, 1H), 4.27 (ddd,J=13.7, 6.8, 2.9 Hz, 1H), 4.41-4.51 (m, 1H), 6.87-6.91 (m, 1H),6.93-6.99 (m, 2H), 7.97 (d, J=8.8 Hz, 1H); MS (DCI/NH₃) m/z 367 (M+H)⁺.Anal. Calculated for C₁₇H₁₉ClN₂O₃S: C, 55.66; H, 5.22; N, 7.64. Found:C, 55.40; H, 5.31; N, 7.48.

Example 2185-chloro-2-methoxy-N-[(2Z)-1-(2-methoxyethyl)-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]benzamideExample 218A 6,7-dihydro-4H-pyrano[4,3-d][1,3]thiazol-2-amine

To a solution of tetrahydro-4H-pyran-4-one (Aldrich) (7.22 g, 72.11mmol) in cyclohexane (70 mL) were added pyrrolidine (6.26 mL, 7.57 mmol)and p-toluenesulfonic acid monohydrate (13.72 mg, 0.07 mmol). Thereaction mixture was refluxed for 3 hours with a Dean-Stark trap, cooledand concentrated. The residue was dissolved in methanol (20 mL) and thensulfur (2.31 g, 72.11 mmol) was added followed by a solution ofcyanamide (3.03 g, 72.11 mmol) in methanol (5 mL) at 0° C. The reactionmixture was stirred at room temperature overnight, filtered,concentrated and purified by column chromatography using an Analogix®Intelliflash280™ (SiO₂, 0-5% methanol in dichloromethane) to afford thetitle compound. MS (ESI⁺) m/z 157 (M+H)⁺.

Example 218B1-(2-methoxyethyl)-6,7-dihydro-1H-pyrano[4,3-d]thiazol-2(4H)-iminehydrobromide

A mixture of product of Example 218A (1.0 g, 6.4 mmol) and 2-bromoethylmethyl ether (3.0 mL, 32.0 mmol) was processed according to the methodof Example 2A to afford the title compound: MS (LC/MS) m/z 213 (M+H)⁺.

Example 218C5-chloro-2-methoxy-N-[(2Z)-1-(2-methoxyethyl)-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]benzamide

To a solution of Example 218B (150.0 mg, 0.51 mmol) in tetrahydrofuran(10 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimidehydrochloride (97.0 mg, 0.51 mmol), 1-hydroxybenzotriazole (69.0 mg,0.51 mmol), triethylamine (178.0 μL, 1.28 mmol), and5-chloro-2-methoxybenzoic acid (Aldrich) (95.0 mg, 0.51 mmol). Themixture was stirred overnight at 80° C., and then diluted with ethylacetate, washed with 1 M aqueous NaHCO₃, dried (Na₂SO₄), filtered andconcentrated. Purification by preparative HPLC on a Waters Symmetry C8column (40 mm×100 mm, 7 μm particle size) using a gradient of 10% to100% acetonitrile: ammonium acetate (10 mM) over 15 minutes at a flowrate of 70 mL/minutes afforded the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 2.75 (t, J=5.4 Hz, 2H), 3.25 (s, 3H), 3.69 (t,J=5.3 Hz, 2H), 3.80 (s, 3H), 3.95 (t, J=5.4 Hz, 1H), 4.27 (t, J=5.3 Hz,2H), 4.58 (s, 2H), 7.12 (d, J=8.8 Hz, 1H), 7.46 (dd, J=9.0, 2.9 Hz, 1H),7.69 (d, J=2.7 Hz, 1H); MS (ESI⁺) m/z 383 (M+H)⁺. Anal. Calculated forC₁₇H₁₉ClN₂O₄S: C, 53.33; H, 5.00; N, 7.32. Found: C, 53.21; H, 4.80; N,7.27.

Example 2195-bromo-2-methoxy-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 219A 5-bromo-2-methoxybenzoic acid

To a solution of 2-methoxybenzoic acid (6 g, 39.4 mmol) in 80 mL ofacetonitrile was added N-bromosuccinimide (7.4 g, 41.4 mmol) in 20 mL ofacetonitrile. The reaction mixture was warmed to ambient temperature andthe mixture was allowed to stir for 16 hours. AdditionalN-bromosuccinimide (14.8 g, 82.8 mmol) was added and the reactionmixture stirred for an additional 48 hours. The mixture was quenchedwith 25 mL of H₂O and the layers were separated. The aqueous layer wasextracted with three 15 mL of portions of CH₂Cl₂ and the combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification via columnchromatography (SiO₂, 50% hexanes in ethyl acetate) afforded the titlecompound. MS (DCI/NH₃) m/z 248, 250 (M+NH₄)⁺.

Example 219B 5-bromo-2-methoxybenzoyl chloride

A solution of Example 219A (0.28 g, 1.4 mmol) in 5 mL of SOCl₂ waswarmed to reflux and was allowed to stir for 2 hours. The mixture wascooled to ambient temperature and concentrated under reduced pressure.The crude material was diluted with 5 mL of toluene and concentratedunder reduced pressure. This dilution with toluene and concentration wasrepeated two additional times to give the crude title compound which wasused without additional purification or characterization.

Example 219C5-bromo-2-methoxy-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamide

Example 208B (0.25 g, 1.3 mmol), triethylamine (0.53 mL, 3.8 mmol) andExample 219B (1.4 mmol) in 15 mL of tetrahydrofuran were processed as inExample 208D to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm1.65-1.80 (m, 1H), 1.85-1.96 (m, 2H), 2.01-2.14 (m, 1H), 2.34 (d, J=1.4Hz, 3H), 3.71-3.80 (m, 1H), 3.85 (s, 3H), 3.85-3.93 (m, 1H), 4.21-4.41(m, 3H), 7.02 (d, J=9.2 Hz, 1H), 7.14 (q, J=1.1 Hz, 1H), 7.53 (dd,J=8.8, 2.7 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H); MS (DCI/NH₃) m/z 411, 413(M+H)⁺. Anal. Calculated for C₁₇H₁₉BrN₂O₃S: C, 49.64; H, 4.66; N, 6.81.Found: C, 49.48; H, 4.53; N, 6.72.

Example 2205-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(2-tetrahydro-2H-pyran-4-ylethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 220A 2-(tetrahydro-2H-pyran-4-yl)ethyl 4-methylbenzenesulfonate

To a solution of 2-(tetrahydropyran-4-yl)-ethanol (1.5 g, 11.5 mmol) in10 mL of CH₂Cl₂ and 7 mL of pyridine was added p-toluenesulfonylchloride (2.4 g, 12.7 mmol) portion wise over 15 minutes. The mixturestirred at ambient temperature for 3 hours and was quenched with 10 mLof saturated, aqueous NaHCO₃. The layers were separated and the aqueouslayer was extracted with three 5 mL of portions of CH₂Cl₂. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification via columnchromatography (SiO₂, 70% hexanes in ethyl acetate) afforded the titlecompound. MS (DCI/NH₃) m/z 302 (M+NH₄)⁺.

Example 220B5-methyl-3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)thiazol-2(3H)-imine

A mixture of Example 220A (1.9 g, 6.7 mmol), 2-amino-5-methylthiazole(0.77 g, 6.7 mmol) and tetrabutylammonium iodide (1.1 g, 3.3 mmol) in 2mL of N,N-dimethylformamide was warmed of 10 to 85° C. and was allowedto stir for 18 hours. The mixture was diluted with 10 mL of CH₂Cl₂,washed with 10 mL of 10% aqueous NaHCO₃, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. Purification viacolumn chromatography (SiO₂, 10% methanol in ethyl acetate then 9:1:0.1CH₂Cl₂:methanol:NH₄OH) afforded the title compound. MS (DCI/NH₃) m/z 227(M+H)⁺.

Example 220C5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(2-tetrahydro-2H-pyran-4-ylethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

Example 220B (0.20 g, 0.9 mmol), triethylamine (0.37 mL, 0.26 mmol) andExample 205B (0.9 mmol) in 10 mL of tetrahydrofuran were processed as inExample 208D to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm1.26-1.44 (m, 2H), 1.47-1.65 (m, 1H), 1.71-1.89 (m, 4H), 2.34 (d, J=1.4Hz, 3H), 3.32-3.41 (m, 2H), 3.86 (s, 3H), 3.86-3.94 (m, 2H), 4.26-4.35(m, 2H), 7.07 (d, J=8.8 Hz, 1H), 7.14 (q, J=1.4 Hz, 1H), 7.40 (dd,J=9.0, 2.9 Hz, 1H), 7.89 (d, J=3.1 Hz, 1H); MS (DCI/NH₃) m/z 395 (M+H)⁺.Anal. Calculated for C₁₉H₂₃ClN₂O₃S: C, 57.79; H, 5.87; N, 7.09. Found:C, 57.54; H, 5.67; N, 7.07.

Example 2215-chloro-N-[(2Z)-5-ethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 221A 5-ethyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-imine

A mixture of 5-ethylthiazol-2-amine and 2-(bromomethyl)tetrahydrofuranwere processed using the method described in Example 2A to afford thetitle compound. MS (ESI) m/z 213 (M+H)⁺.

Example 221B5-chloro-N-[(2Z)-5-ethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 221A and 5-chloro-2-methoxybenzoic acid were processed using themethod described in Example 2B to afford the title compound. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ ppm 1.21 (t, J=7.63 Hz, 3H) 1.59-1.68 (m,1H) 1.77-1.85 (m, 2H) 1.89-1.97 (m, 1H) 2.67 (dd, J=15.56, 7.63 Hz, 2H)3.65 (dd, J=14.95, 7.02 Hz, 1H) 3.75-3.82 (m, 1H) 3.78 (s, 3H) 4.13-4.24(m, 2H) 4.24-4.30 (m, 1H) 7.10 (d, J=8.85 Hz, 1H) 7.26 (t, J=1.22 Hz,1H), 7.44 (dd, J=8.85, 2.75 Hz, 1H) 7.64 (d, J=2.75 Hz, 1H); MS (ESI)m/z 381 (M+H)⁺.

Example 2225-chloro-2-methoxy-N-[(2Z)-5-propyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 222A5-propyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-imine

A mixture of 5-propylthiazol-2-amine and 2-(bromomethyl)tetrahydrofuranwere processed using the method described in Example 2A to afford thetitle compound. MS (ESI) m/z 227 (M+H)⁺.

Example 222B5-chloro-2-methoxy-N-[(2Z)-5-propyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

Example 222A and 5-chloro-2-methoxybenzoic acid were processed using themethod described in Example 2B to afford the title compound. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ ppm 0.93 (t, J=7.32 Hz, 3H) 1.56-1.67 (m,3H) 1.77-1.85 (m, 2H) 1.93 (dt, J=19.22, 7.02 Hz, 1H) 2.62 (t, J=7.02Hz, 2H) 3.65 (dd, J=14.95, 6.71 Hz, 1H) 3.74-3.80 (m, 1H) 3.77-3.79 (m,3H) 4.15-4.24 (m, 2H) 4.24-4.30 (m, 1H) 7.10 (d, J=8.85 Hz, 1H)7.25-7.28 (m, 1H) 7.44 (dd, J=8.85, 2.75 Hz, 1H) 7.64 (d, J=2.75 Hz,1H); MS (ESI) m/z 395 (M+H)⁺.

Example 2235-chloro-N-[(2Z)-5-chloro-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 223A 5-chloro-N-(5-chlorothiazol-2-yl)-2-methoxybenzamide

A mixture of 5-chlorothiazol-2-amine hydrochloride (513 mg, 3 mmol),5-chloro-2-methoxybenzoic acid (670 mg, 3.6 mmol),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (1.15 g,6 mmol), 1-hydroxybenzotriazole hydrate (810 mg, 6 mmol) and4-(dimethylamino)pyridine (73 mg, 0.6 mmol) in pyridine was stirred atroom temperature for 2 hours. The volatiles were removed under vacuum,and the resulting mixture was diluted with water and extracted withethyl acetate. The organic extract was dried (Na₂SO₄), filtered andconcentrated. The residue was washed with a small amount of ethylacetate, and filtered to afford the title compound. MS (ESI) m/z 303(M+H)⁺.

Example 223B5-chloro-N-[(2Z)-5-chloro-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 223A (250 mg, 0.83 mmol) intetrahydrofuran/N,N-dimethylformamide (1:2) (9 mL) was treated with NaH(60%) (40 mg, 1.0 mmol) for 10 minutes then 2-mL) was treated with NaH(60%) (40 mg, 1.0 mmol) for 10 minutes then2-(bromomethyl)tetrahydrofuran (164 mg, 1.0 mmol) was added. The mixturewas heated at 150° C. for ethyl acetate. The organic extract was dried(Na₂SO₄), filtered and concentrated. Purification by reverse phase HPLCafforded the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δppm 1.60-1.70 (m, 1H) 1.79-1.89 (m, 2H) 1.92-2.01 (m, 1H) 3.66 (dd,J=15.04, 7.06 Hz, 1H) 3.76-3.83 (m, 1H) 3.79-3.81 (m, 3H) 4.15-4.23 (m,1H) 4.24-4.33 (m, 2H) 7.14 (d, J=8.90 Hz, 1H) 7.49 (dd, J=8.90, 2.76 Hz,1H) 7.74 (d, J=3.07 Hz, 1H) 7.77 (s, 1H). MS (ESI) m/z 387 (M+H)⁺.

Example 2244,5-dichloro-2-methoxy-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 224A 4,5-dichloro-2-methoxybenzoic acid

To a solution of 4-chloro-2-methoxybenzoic acid (5 g, 26.8 mmol) in 200mL of acetonitrile ambient temperature and was quenched with 50 mL ofH₂O. The layers were separated and the aqueous layer was extracted withthree 25 mL portions of CH₂Cl₂. The combined organic extracts were driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification via column chromatography (SiO₂, 25% hexanes in ethylacetate) afforded the title compound. MS (DCI/NH₃) m/z 238 (M+NH₄)⁺.

Example 224B 4,5-dichloro-2-methoxybenzoyl chloride

A solution of Example 224A (0.18 g, 0.81 mmol) in 5 mL of SOCl₂ waswarmed to reflux and under reduced pressure. The crude material wasdiluted with 5 mL of toluene and concentrated under reduced pressure.This dilution with toluene and concentration was repeated two additionaltimes to afford the title compound which was used without additionalpurification or characterization.

Example 224C4,5-dichloro-2-methoxy-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamide

Example 208B (0.16 g, 0.81 mmol), triethylamine (0.34 mL, 2.4 mmol) andExample 224B compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.64-1.79 (m, 1H),1.83-1.96 (m, 2H), 2.03-2.15 (m, 1H), 2.34 (d, J=1.4 Hz, 3H), 3.70-3.80(m, 1H), 3.83-3.93 (m, 1H), 3.87 (s, 3H), 4.20-4.44 (m, 3H), 7.15 (q,J=1.1 Hz, 1H), 7.26 (s, 1H), 7.99 (s, 1H); MS (DCI/NH₃) m/z 401 (M+H)⁻.Anal. Calculated for C₁₇H₁₈Cl₂N₂O₃S: C, 50.88; H, 4.52; N, 6.98. Found:C, 50.63; H, 4.41; N, 6.83.

Example 2255-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(tetrahydro-2H-pyran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 225A (tetrahydro-2H-pyran-3-yl)methyl 4-methylbenzenesulfonate

To a solution of (tetrahydropyran-3-yl)-methanol (Matrix, 1.67 g, 14.4mmol) in 15 mL of CH₂Cl₂ and 15 mL of pyridine was addedp-toluenesulfonyl chloride (2.9 g, 15.1 mmol) in portions over 10minutes. The mixture stirred at ambient temperature for 18 hours and wasquenched with 10 mL of saturated, aqueous NaHCO₃. The layers wereseparated and the aqueous phase was extracted three 5 mL of portions ofCH₂Cl₂. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. Purification viacolumn chromatography (SiO₂, 70% hexanes in ethyl acetate) afforded thetitle compound. MS (DCI/NH₃) m/z 288 (M+NH₄)⁺.

Example 225B5-methyl-3-((tetrahydro-2H-pyran-3-yl)methyl)thiazol-2(3H)-imine

A mixture of Example 225A (1.0 g, 3.7 mmol), 2-amino-5-methylthiazole(0.42 g, 3.7 mmol) and tetrabutylammonium iodide (0.68 g, 1.85 mmol) in1 mL of N,N-dimethylformamide was warmed to 85° C. and was allowed tostir for 16 hours. The mixture was diluted with 10 mL of CH₂Cl₂, washedwith 10 mL of 10% aqueous NaHCO₃, dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. Purification via columnchromatography (SiO₂, 10% methanol in ethyl acetate then 9:1:0.1CH₂Cl₂:methanol:NH₄OH) afforded the title compound. MS (DCI/NH₃) m/z 213(M+H)⁺.

Example 225C5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(tetrahydro-2H-pyran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

Example 225B (0.19 g, 0.89 mmol), triethylamine (0.29 mL, 2.1 mmol) andExample 205B (0.63 mmol) in 10 mL of tetrahydrofuran were processed asin Example 208D to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δppm 1.33-1.49 (m, 1H), 1.50-1.67 (m, 1H), 1.69-1.86 (m, 2H), 2.20-2.32(m, 1H), 2.34 (d, J=1.4 Hz, 3H), 3.32-3.38 (m, 1H), 3.50 (ddd, J=11.5,9.5, 3.1 Hz, 1H), 3.72-3.82 (m, 2H), 3.86 (s, 3H), 4.17 (d, J=7.5 Hz,2H), 7.07 (d, J=8.8 Hz, 1H), 7.11 (q, J=1.4 Hz, 1H), 7.40 (dd, J=8.8,2.7 Hz, 1H), 7.85 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 381 (M+H)⁺. Anal.Calculated for C₁₈H₂₁ClN₂O₃S: C, 56.76; H, 5.56; N, 7.35. Found: C,56.84; H, 5.32; N, 7.29.

Example 2262-chloro-N-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]nicotinamide

A mixture of Example 186A (0.15 g), 2-chloronicotinic acid (99 mg),1-hydroxybenzotriazole hydrate (80 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (120 mg)and triethylamine (0.15 mL) in N,N-dimethylformamide was stirredovernight at room temperature, poured into water and extracted withether (3×). The combined organic extracts were dried (Na₂SO₄), filteredand the solvent evaporated. The crude material was purified by gradientflash chromatography over silica gel eluting with ethyl acetate:hexane(1:4 to 1:1) to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.65 (m, 1H), 1.85 (m, 2H), 2.0 (m, 1H),2.25 (s, 3H), 2.28 (s, 3H), 3.62 (dd, 1H), 3.77 (dd, 1H), 4.08 (dd, 1H),4.28 (m, 1H), 4.38 (dd, 1H), 7.50 (dd, 1H), 8.24 (dd, 1H), 8.45 (dd,1H); MS (ESI+) m/z 352 (M+H)⁺.

Example 2275-chloro-N-[(2Z)-4,5-dimethyl-3-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 227A 3-allyl-4,5-dimethylthiazol-2(3H)-imine hydrobromide

A mixture of 4,5-dimethyl-1,3-thiazol-2-amine (1 g) and allylbromide(0.95 g) in toluene (5 mL) was heated to 85° C. for 12 hours, cooled,diluted with ether, filtered and the solvent was evaporated to affordcrude product that was taken on to the next step without furthercharacterization.

Example 227B(Z)—N-(3-allyl-4,5-dimethylthiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

A mixture of Example 227A (1.3 g), Example 205B (1.36 g) andtriethylamine (1.0 g) in tetrahydrofuran (40 mL) was heated to 60° C.for 4 hours, cooled and solvent was evaporated. The crude material wastriturated with ether, filtered and solvent evaporated. The crude wasflash chromatographed over silica gel gradient eluting with ethylacetate:hexane (2:3 to 3:2) to afford the title compound. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ ppm 2.22 (s, 3H), 2.23 (s, 3H), 3.78 (s,3H), 4.85 (m, 2H), 4.96, (dq, J=17.3, 1.3 Hz, 1H), 5.19 (dq, J=10.5, 1.3Hz, 1H), 5.92-6.05 (m, 1H), 7.10 (d, 1H), 7.44 (dd, 1H), 7.66 (d, 1H);MS (ESI+) m/z 337 (M+H)⁺.

Example 227C5-chloro-N-[(2Z)-4,5-dimethyl-3-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

To a solution of acetaldoxime (56 mg, 1.48 mmol) in CHCl₃ (10 mL) underN₂ was added N-chlorosuccinimide (200 mg) and pyridine (10 μL). After4.5 hours at room temperature, Example 227B (100 mg) was added, followedby triethylamine (0.15 g) and the reaction continued to stir at roomtemperature for 21 hours. The reaction mixture was washed with water andpartitioned. The aqueous layer was extracted again with CH₂Cl₂ and thecombined organic extracts were dried (MgSO₄), filtered, and solventevaporated. The crude was purified by flash chromatography over silicagel eluting with ethyl acetate:hexane (1:1) to afford the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.93 (s, 3H),2.23 (s, 6H), 2.90 (dd, 1H), 3.14 (dd, 1H), 3.79 (s, 3H), 4.11 (dd, 1H),4.27, (dd, 1H), 4.98 (m, 1H), 7.11 (d, 1H), 7.44 (dd, 1H), 7.67 (d, 1H).MS (ESI+) m/z 394 (M+H)⁺.

Example 228N-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-4-(trifluoromethyl)nicotinamide

Example 186A (0.15 g) and 4-(trifluoromethyl)nicotinic acid (0.12 g)were processed according to the method of Example 226. The crude waspurified by reverse phase preparative HPLC on a Waters Symmetry C8column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10minutes run time) at a flow rate of 40 mL/minutes) to afford the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.63 (m, 1H),1.85 (m, 2H), 1.96 (m, 1H), 2.25 (s, 3H), 2.29 (s, 3H), 3.62 (dd, 1H),3.77 (dd, 1H), 4.07 (dd, 1H), 4.25 (m, 1H), 4.38 (dd, 1H), 7.80 (d, 1H),8.89 (d, 1H), 9.12 (s, 1H). MS (ESI+) m/z 386 (M+H)⁺.

Example 229N-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-ethoxynicotinamide

Example 186A (0.15 g) and 2-ethoxynicotinic acid (0.1 g) were processedaccording to the method of Example 226. The crude was purified byreverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 μm particle size) using a gradient of 10% to 100%acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10minutes run time) at a flow rate of 40 mL/minutes) to afford the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.32 (t, 3H),1.66 (m, 1H), 1.85 (m, 2H), 1.97 (m, 1H), 2.22 (s, 3H), 2.26 (s, 3H),3.62 (dd, 1H), 3.78 (dd, 1H), 4.06 (dd, 1H), 4.3-4.42 (m, 3H), 7.02 (dd,1H), 8.13 (dd, 1H), 8.22 (dd, 1H). MS (ESI+) m/z 362 (M+H)⁺.

Example 230N-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2,3,6-trifluoroisonicotinamide

Example 186A (0.15 g) and 2,3,6-trifluoroisonicotinic acid (0.11 g) wereprocessed according to the method of Example 226. The crude was purifiedby reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm×100 mm, 7 μm particle size) using a gradient of 10% to 100%acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10minutes run time) at a flow rate of 40 mL/minutes) to afford the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.67 (m, 1H),1.86 (m, 2H), 2.00 (m, 1H), 2.27 (s, 3H), 2.30 (s, 3H), 3.62 (dd, 1H),3.78 (dd, 1H), 4.15 (dd, 1H), 4.28 (m, 1H), 4.43 (dd, 1H), 7.57 (t, 1H).MS (ESI+) m/z 372 (M+H)⁺.

Example 2316-chloro-N-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-4-(trifluoromethyl)nicotinamide

Example 186A (0.15 g) and 6-chloro-4-(trifluoromethyl)nicotinic acid(0.17 g) were processed according to the method of Example 226. Thecrude was purified by reverse phase preparative HPLC on a WatersSymmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradientof 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8minutes (10 minutes run time) at a flow rate of 40 mL/minutes) to affordthe title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.62(m, 1H), 1.85 (m, 2H), 1.96 (m, 1H), 2.25 (s, 3H), 2.29 (s, 3H), 3.62(dd, 1H), 3.77 (dd, 1H), 4.08 (dd, 1H), 4.24 (m, 1H), 4.38 (dd, 1H),7.99 (s, 1H), 9.00 (s, 1H); MS (ESI+) m/z 420 (M+H)⁺.

Example 2325-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 232A 3-allyl-5-methylthiazol-2(3H)-imine hydrobromide

A mixture of 2-amino-5-methylthiazole (2.5 g) and allylbromide (3.31 g)was processed according to the method of Example 227A to afford thetitle compound that was taken directly to the next step. MS (ESI+) m/z155 (M+H)⁺.

Example 232B(Z)—N-(3-allyl-5-methylthiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

A mixture of Example 232A (0.5 g) and 5-chloro-2-methoxybenzoylchloride(0.57 g) were processed according to the method of Example 227B toafford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm2.28 (d, J=1.4 Hz, 3H), 3.78 (s, 3H), 4.77 (d, 2H), 5.13 (dq, J=16.9,1.3 Hz, 1H), 5.24 (dq, J=10.5, 1.4 Hz, 2H), 5.94-6.07 (m, 1H), 7.11 (d,1H), 7.23 (q, J=1.4 Hz, 1H), 7.43 (dd, 1H), 7.68 (d, 1H); MS (ESI+) m/z323 (M+H)⁺.

Example 232C5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]benzamide

Example 232B was processed according to the method of Example 227C toafford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm1.90 (s, 3H), 2.28 (s, 3H), 2.87 (dd, 1H), 3.11 (dd, 1H), 4.23 (d, 2H),4.94 (m, 1H), 7.11 (d, 1H), 7.25 (s, 1H), 7.45 (dd, 1H), 7.67 (d, 1H);MS (ESI+) m/z 380 (M+H)⁺.

Example 233N-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-(ethylamino)benzamide

Example 186A (0.15 g) and 2-ethylaminobenzoic acid (Pellon Syn. Lett.2005, 10, 1606) (0.1 g) were processed according to the method ofExample 226. The crude was purified by flash chromatography over silicagel gradient eluting with ethyl acetate:hexane (1:9 to 1:3) to affordthe title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.25(t, 3H), 1.70 (m, 1H), 1.87 (m, 2H), 2.01 (m, 1H), 2.20 (s, 3H), 2.26(s, 3H), 3.20 (m, 2H), 3.62 (dd, 1H), 3.79 (dd, 1H), 4.12 (dd, 1H), 4.28(m, 1H), 4.38 (dd, 1H), 6.55 (t, 1H), 6.67 (d, 1H), 7.27 (t, 1H), 8.22(dd, 1H), 8.52 (t, 1H); MS (ESI+) m/z 360 (M+H)⁺.

Example 234N-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-iodo-2-(methylamino)benzamide

Example 186A (0.15 g) and 5-iodo-2-methylaminobenzoic acid (0.17 g) wereprocessed according to the method of Example 226. The crude was purifiedby flash chromatography over silica gel gradient eluting with ethylacetate:hexane (1:19 to 1:10) to afford the title compound. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ ppm 1.7-1.82 (m, 1H), 1.84-1.95 (m, 2H),1.95-2.08 (m, 1H), 2.22 9 s, 3H), 2.27 (s, 3H), 2.84 (d, 3H), 3.65 (dd,1H), 3.82 (dd, 1H), 4.12 (dd, 4.28 (m, 1H), 4.36 (dd, 1H), 6.52 (d, 1H),7.53 (dd, 1H), 8.46 (d, 1H), 8.52 (q, 1H); MS (ESI+) m/z 472 (M+H)⁺.

Example 2355-bromo-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

To a mixture of 3,3-dimethylbutyraldehyde (Aldrich) (5 mL, 39.8 mmol)and Example 278A (641.0 mg, 4.0 mmol) was added a mixture ofdimethylsulfoxide (560 μL, 8 mmol) and 12 N aqueous HCl (667 μL, 8mmol). The reaction mixture was heated at 40° C. overnight. The mixturewas concentrated and the residue was dried under vacuum for 2 hours. Theresidue (252 mg 0.9 mmol) was dissolved in tetrahydrofuran (10 mL). Tothis solution was added 5-bromo-2-methoxy-benzoic acid (209.0 mg, 0.9mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (73mg, 0.9 mmol), 1-hydroxybenzotriazole (122.0 mg, 0.9 mmol) andtriethylamine (315.0 μL, 2.3 mmol). The mixture was stirred overnight at80° C., and cooled to room temperature. The mixture was diluted withethyl acetate, washed with 1 M aqueous NaHCO₃, dried (Na₂SO₄), filteredand concentrated. The residue was purified by flash chromatography usingan Analogix® Intelliflash280™ (SiO₂, 0-75% ethyl acetate in hexanes) toafford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 1.32(s, 9H), 1.58-1.71 (m, 1H), 1.75-1.86 (m, 2H), 1.87-2.00 (m, 1H), 3.64(dd, J=15, 6.8 Hz, 1H), 3.78 (s, 3H), 3.79-3.83 (m, 1H), 4.19 (d, J=5.8Hz, 2H), 4.23-4.35 (m, 1H), 7.05 (d, J=8.8 Hz, 1H), 7.25 (s, 1H), 7.56(dd, J=8.8, 2.7 Hz, 1H), 7.76 (d, J=2.7 Hz, 1H.

Example 2365-chloro-2-(cyclopropyloxy)-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 236A methyl 5-chloro-2-(2-chloroethoxy)benzoate

A mixture of methyl-5-chlorosalicylate (19.5 g, 105 mmol), 2-chloroethylp-toluenesulfonate (19.3 mL, 107 mmol) and K₂CO₃ (28.9 g, 210 mmol) in105 mL of N,N-dimethylformamide was warmed to 50° C. and allowed to stirfor 18 hours. The mixture was cooled to ambient temperature, dilutedwith 25 mL of ethyl acetate and 25 mL of H₂O. The layers were separatedand the organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification via columnchromatography (SiO₂, 75% hexanes in ethyl acetate) afforded the titlecompound. MS (DCI/NH₃) m/z 249 (M+H)⁺, 266 (M+NH₄)⁺.

Example 236B 5-chloro-2-(vinyloxy)benzoic acid

To Example 236A (15 g, 60 mmol) in 100 mL of tetrahydrofuran at 0° C.was added potassium t-butoxide (8.9 g, 75.6 mmol) portion wise with theinternal reaction temperature being maintained below 5° C. After theaddition was complete, the mixture was allowed to warm to ambienttemperature and was allowed to stir for 18 hours. The mixture wasdiluted with 25 mL of H₂O and 25 mL of ethyl acetate and the layers wereseparated. The aqueous layer was acidified with 1 N aqueous HCl to pH 7and was extracted with three 15 mL portions of ethyl acetate. Theseorganic extracts (excluding the original organic layer beforeacidification) were combined and dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to afford the title compound. MS(DCI/NH₃) m/z 216 (M+NH₄)⁺.

Example 236C methyl 5-chloro-2-(vinyloxy)benzoate

To Example 236B (5.1 g, 26 mmol) in 30 mL of N,N-dimethylformamide wasadded K₂CO₃ (10.7 g, 78 mmol) followed by CH₃I (1.8 mL, 29 mmol). Themixture stirred at ambient temperature for 3 hours and was diluted with20 mL of H₂O and 20 mL of ether. The layers were separated and theaqueous layer was extracted twice with 10 mL of ether. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification via columnchromatography (SiO₂, 75% hexanes in ethyl acetate) afforded the titlecompound. MS (DCI/NH₃) m/z 213 (M+H)⁺, 230 (M+NH₄)⁺.

Example 236D methyl 5-chloro-2-cyclopropoxybenzoate

To a solution of Example 236C (1.29 g, 6.1 mmol) in 15 mL ofdichloroethane at −5° C. was added chloro-iodomethane (1.4 mL, 19.4mmol) A solution of diethylzinc (1M solution in hexanes, 9.7 mL, 9.7mmol) was added dropwise over 1 hour using a syringe pump. After theaddition was complete, the mixture was allowed to warm to ambienttemperature and was stirred for 45 minutes. The mixture was cooled to 0°C. and quenched with 5 mL of saturated, aqueous NH₄Cl and 1 mL ofconcentrated NH₄OH. This mixture was diluted with 10 mL of ethyl acetateand the layers were separated. The aqueous layer was extracted twicewith 10 mL of ethyl acetate and the combined organic extracts were driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification via column chromatography (SiO₂, 75% hexanes in ethylacetate) afforded the title compound. MS (DCI/NH₃) m/z 227 (M+H)⁺, 244(M+NH₄)⁺.

Example 236E 5-chloro-2-cyclopropoxybenzoic acid

To a solution of Example 236D (1.24 g, 5.5 mmol) in 10 mL of ethanol atambient temperature was added 5 mL of 40% aqueous KOH. The mixture wasstirred at ambient temperature for 2 hours and was partiallyconcentrated to remove the ethanol. The aqueous residue was extractedwith three 10 mL of portions of CH₂Cl₂. The aqueous layer was acidifiedwith 10% aqueous HCl to ˜pH 1 and then extracted with three 10 mL ofportions of CH₂Cl₂. The combined organic extracts (from bothextractions) were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to afford the title compound. MS (DCI/NH₃) m/z213 (M+H)⁺, 230 (M+NH₄)⁺.

Example 236F5-chloro-2-(cyclopropyloxy)-N-[(2Z)-5-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamide

A mixture of Example 236E (0.30 g, 1.4 mmol) and1,1′-carbonyldiimidazole (0.27 g, 1.7 mmol) in 10 mL of ethyl acetatewas stirred at ambient temperature for 4 hours. Example 208B (0.28 g,1.4 mmol) in 2 mL of ethyl acetate and 2 mL of tetrahydrofuran was addedand the mixture was warmed to reflux for 16 hours. The mixture wascooled to ambient temperature and was quenched with 10 mL of H₂O and 5mL 5% aqueous HCl and was diluted with 10 mL of ethyl acetate. Thelayers were separated and the aqueous layer was extracted twice with 5mL of ethyl acetate. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification via column chromatography (SiO₂, 40% hexanes in ethylacetate) afforded the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm0.76-0.82 (m, 2H), 1.63-1.77 (m, 1H), 1.84-1.96 (m, 2H), 2.01-2.14 (m,1H), 2.33 (d, J=1.4 Hz, 3H), 3.69-3.93 (m, 4H), 4.18-4.43 (m, 4H), 7.13(q, J=1.4 Hz, 1H), 7.38-7.41 (m, 2H), 7.74 (dd, J=2.0, 1.0 Hz, 1H); MS(DCI/NH₃) m/z 393 (M+H)⁺. Anal. Calculated for C₁₉H₂₁ClN₂O₃S: C, 58.08;H, 5.39; N, 7.13. Found: C, 57.77; H, 5.45; N, 7.09.

Example 2375-chloro-N-[(2Z)-3-(1,4-dioxan-2-ylmethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 237A 3-((1,4-dioxan-2-yl)methyl)-5-methylthiazol-2(3H)-imine

A mixture of 2-amino-5-methylthiazole (0.77 g, 6.7 mmol) and2-iodomethyl-1,4-dioxane (Synchem-OHG, 1.5 g, 6.7 mmol) was warmed to85° C. and was allowed to stir for 18 hours. The mixture was cooled toambient temperature and the crude material was purified via columnchromatography (SiO₂, 10% methanol in ethyl acetate then 9:1:0.1CH₂Cl₂:methanol:NH₄OH) to afford the title compound. MS (DCI/NH₃) m/z215 (M+H)⁺.

Example 237B5-chloro-N-[(2Z)-3-(1,4-dioxan-2-ylmethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 237A (0.20 g, 0.93 mmol), triethylamine (0.39 mL, 2.8 mmol) andExample 205B (0.93 mmol) in 10 mL of tetrahydrofuran were processed asdescribed in Example 208D to afford the title compound. ¹H NMR (300 MHz,CD₃OD) δ ppm 2.33 (d, J=1.4 Hz, 3H), 3.34 (dd, J=11.5, 9.5 Hz, 1H),3.50-3.71 (m, 3H), 3.82 (dt, J=10.5, 3.1 Hz, 2H), 3.86 (s, 3H),3.99-4.09 (m, 1H), 4.19-4.36 (m, 2H), 7.08 (d, J=8.8 Hz, 1H), 7.09 (q,J=1.0 Hz, 1H), 7.40 (dd, J=9.0, 2.9 Hz, 1H), 7.81 (d, J=2.7 Hz, 1H); MS(DCI/NH₃) m/z 383 (M+H)⁺. Anal. Calculated for C₁₇H₁₉ClN₂O₄S: C, 53.33;H, 5.00; N, 7.32. Found: C, 53.51; H, 4.93; N, 7.29.

Example 238N-[(2Z)-5-acetyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 238AN-(5-acetyl-4-methylthiazol-2-yl)-5-chloro-2-methoxybenzamide

To a solution of 5-acetyl-2-amino-4-methylthiazole (5.0 g, 32 mmol) in50 mL of tetrahydrofuran was added triethylamine (13.4 mL, 96 mmol)followed by Example 205B (32 mmol) in 10 mL of tetrahydrofuran viacannula. The mixture was warmed to 50° C. and was allowed to stir for 18hours. The mixture was cooled to ambient temperature quenched with 15 mLof NH₄Cl and diluted with 15 mL of ethyl acetate. The layers wereseparated and the aqueous layer was extracted with three 10 mL ofportions of ethyl acetate. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was washed with ethyl acetate and the remaining solids were puretitle compound. MS (DCI/NH₃) m/z 325 (M+H)⁺.

Example 238BN-[(2Z)-5-acetyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A mixture of Example 238A (1.1 g, 3.2 mmol), Example 208A (1.0 g, 3.9mmol), tetrabutylammonium iodide (0.36 g, 0.98 mmol) and potassiumt-butoxide (0.58 g, 4.9 mmol) in 12 mL of N,N-dimethylformamide waswarmed to 65° C. and was allowed to stir for 16 hours. The mixture wascooled to ambient temperature quenched with 10 mL of NH₄Cl and dilutedwith 10 mL of ethyl acetate. The layers were separated and the aqueouslayer was extracted twice with 10 mL of ethyl acetate. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification via columnchromatography (SiO₂, 30% hexanes in ethyl acetate) afforded the titlecompound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.73-1.87 (m, 1H), 1.89-2.05 (m,2H), 2.09-2.22 (m, 1H), 2.52 (s, 3H), 2.79 (s, 3H), 3.69-3.78 (m, 1H),3.85-3.94 (m, 1H), 3.88 (s, 3H), 4.21-4.31 (m, 1H), 4.38-4.49 (m, 1H),4.59 (dd, J=13.9, 3.1 Hz, 1H), 7.10 (d, J=9.2 Hz, 1H), 7.44 (dd, J=8.8,2.7 Hz, 1H), 7.94 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 409 (M+H)⁺. Anal.Calculated for C₁₉H₂₁ClN₂O₄S.0.12H₂O: C, 55.52; H, 5.21; N, 6.81. Found:C, 55.83; H, 5.21; N, 6.41.

Example 2395-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

To Example 238B (0.11 g, 0.27 mmol) in 5 mL of tetrahydrofuran at −78°C. was added a solution of methyl lithium (1.6 M in ether, 0.50 mL, 0.81mmol) dropwise over 5 minutes. The mixture stirred at −78° C. for 1 hourand was slowly warmed to ambient temperature and was allowed to stir for18 hours. The mixture was quenched with 5 mL of NH₄Cl and diluted with 5mL of ethyl acetate. The layers were separated and the aqueous layer wasextracted twice with 5 mL of ethyl acetate. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. Purification via column chromatography (SiO₂,20% hexanes in ethyl acetate) afforded the title compound. ¹H NMR (300MHz, CD₃OD) δ ppm 1.26 (none, 1H), 1.61 (s, 6H), H), 1.73-1.85 (m, 1H),1.88-2.01 (m, 2H), 2.05-2.19 (m, 1H), 2.52 (s, 3H), 3.69-3.78 (m, 1H),3.85 (s, 3H), 3.87-3.93 (m, 1H), 4.02-4.19 (m, 2H), 4.36-4.45 (m, 1H),4.50 (dd, J=13.9, 3.1 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 7.39 (dd, J=8.8,2.7 Hz, 1H), 7.83 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 425 (M+H)⁺. Anal.Calculated for C₂₀H₂₅ClN₂O₄S.0.1H₂O: C, 56.29; H, 5.95; N, 6.56. Found:C, 55.95; H, 5.87; N, 6.47.

Example 240N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 240A 5-tert-butylthiazol-2-amine

To a solution of 3,3-dimethylbutyraldehyde (10 g, 99.8 mmol) in 200 mLof cyclohexane was added pyrrolidine (8.7 mL, 0.11 mol) followed byp-toluenesulfonic acid monohydrate (0.95 g, 5.0 mmol). This reactionflask was equipped with a Dean-Stark trap and the mixture was warmed toreflux and was allowed to stir for 3 hours. The mixture was cooled toambient temperature, filtered and concentrated under reduced pressure.The residue was dissolved in 75 mL of CH₃OH, sulfur was added (3.2 g,99.8 mmol), and the mixture was cooled to 0° C. Cyanamide (4.2 g, 99.8mmol) was added portion wise over 10 minutes and the mixture was allowedto warm to ambient temperature and stir for 18 hours. The reactionmixture was concentrated under reduced pressure and purified by columnchromatography (SiO₂, ethyl acetate then 10% methanol in ethyl acetate)to afford the title compound. MS (DCI/NH₃) m/z 157 (M+H)⁺.

Example 240B (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (R)-tetrahydrofurfuryl alcohol (Lancaster, 1.0 g, 9.8mmol) in 5 mL of CH₂Cl₂ and 5 mL of pyridine was added p-toluenesulfonylchloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture wasstirred at ambient temperature for 3 hours and was quenched with 5 mL ofsaturated, aqueous NaHCO₃. The layers were separated and the aqueouslayer was extracted with three 5 mL of portions of CH₂Cl₂. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound. MS(DCI/NH₃) m/z 257 (M+H)⁺, 274 (M+NH₄)⁺.

Example 240C(R)-5-tert-butyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-imine4-methylbenzenesulfonate

A mixture of Example 240A (9.8 g, 62.7 mmol), Example 240B (23.5 g, 91.7mmol) and tetrabutylammonium iodide (11.6 g, 31.4 mmol) in 35 mL ofN,N-dimethylformamide was warmed to 85° C. and was allowed to stir for72 hours. The mixture was diluted with 50 mL of CH₂Cl₂ and the layerswere separated. The organic layer was washed with 15 mL of saturated,aqueous NaHCO₃ and the combined aqueous layers were extracted with three10 mL of portions of CH₂Cl₂. The combined organic extracts were driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification via column chromatography (SiO₂, 10% methanol in ethylacetate then 9:1:0.1 CH₂Cl₂:methanol:NH₄OH) afforded the title compound.MS (DCI/NH₃) m/z 241 (M+H)⁺.

Example 240D 5-chloro-2-methoxybenzoyl chloride

A solution of 2-methoxy-5-chlorobenzoic acid (6.9 g, 37 mmol) in 15 mLof SOCl₂ was warmed to reflux and was allowed to stir for 2 hours. Themixture was cooled to ambient temperature and concentrated under reducedpressure. The crude material was diluted with 5 mL of toluene andconcentrated under reduced pressure. This dilution with toluene andconcentration was repeated two additional times to afford the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 3.82 (s, 3H),7.16 (d, J=8.8 Hz, 1H), 7.49-7.59 (m, 1H), 7.61 (d, J=2.7 Hz, 1H).

Example 240EN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

To a solution of Example 240C (13.9 g, 34 mmol) in 120 mL oftetrahydrofuran at ambient temperature was added triethylamine (19 mL,135 mmol) followed by Example 240D (7.6 g, 37 mmol) in 30 mL oftetrahydrofuran via cannula. This mixture was warmed to 60° C. and wasallowed to stir for 3 hours and was quenched with 30 mL of NH₄Cl anddiluted with 50 mL of ethyl acetate. The layers were separated and theaqueous layer was extracted with three 5 mL of portions of ethylacetate. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. Purification via flashcolumn chromatography (SiO₂, 50% hexanes:ethyl acetate) afforded thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.35 (s, 9H), 1.64-1.92(m, 3H), 2.00-2.14 (m, 1H), 3.72-3.88 (m, 2H), 3.90 (s, 3H), 4.19-4.34(m, 2H), 4.40 (dd, J=12.9, 2.4 Hz, 1H), 6.86 (s, 1H), 6.90 (d, J=9.2 Hz,1H), 7.32 (dd, J=9.0, 2.9 Hz, 1H), 7.95 (d, J=3.1 Hz, 1H); MS (DCI/NH₃)m/z 409 (M+H)⁺. Anal. Calculated for C₂₀H₂₅ClN₂O₃S: C, 58.74; H, 6.16;N, 6.85. Found: C, 58.74; H, 6.27; N, 6.81.

Example 241N-[(2Z)-5-tert-butyl-3-(1,3-dioxolan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 241A3-((1,3-dioxolan-2-yl)methyl)-5-tert-butylthiazol-2(3H)-imine

A mixture of Example 240A (0.17 g, 1.1 mmol) and2-bromomethyl-1,3-dioxolane (0.21 g, 1.2 mmol) was warmed to 85° C. andwas allowed to stir for 18 hours. The mixture was cooled to ambienttemperature and the crude material was purified via flash columnchromatography (SiO₂, 10% methanol in ethyl acetate then 9:1:0.1CH₂Cl₂:methanol:NH₄OH) to afford the title compound. MS (DCI/NH₃) m/z243 (M+H)⁺.

Example 241BN-[(2Z)-5-tert-butyl-3-(1,3-dioxolan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 241A (64 mg, 0.26 mmol), triethylamine (0.11 mL, 0.79 mmol) andExample 205B (0.26 mmol) in 2 mL of tetrahydrofuran and 0.5 mL ofN,N-dimethylformamide were processed as in Example 208D to afford thetitle compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.38 (s, 9H), 3.86 (s,3H), 3.88-3.98 (m, 4H), 4.42 (d, J=4.1 Hz, 2H), 5.29 (dd, J=4.1 Hz, 1H),7.07 (d, J=8.8 Hz, 1H), 7.12 (s, 1H), 7.40 (dd, J=9.0, 2.9 Hz, 1H), 7.87(d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 411 (M+H)⁺. Anal. Calculated forC₁₉H₂₃ClN₂O₄S: C, 55.54; H, 5.64; N, 6.82. Found: C, 55.43; H, 5.60; N,6.62.

Example 2425-chloro-N-[(2Z)-5-chloro-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 242A 5-chloro-N-(5-chlorothiazol-2-yl)-2-methoxybenzamide

A mixture of 2-amino-5-chlorothiazole hydrochloric acid (1.0 g, 5.9mmol), 5-chloro-2-methoxybenzoic acid (1.3 g, 7.0 mmol),1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (Chem-ImpexInternational, 2.2 g, 12 mmol), 1-hydroxbenzotriazole (0.95 g, 7.0 mmol)and 4-dimethylaminopyridine (0.14 g, 1.2 mmol) in 6 mL of pyridine wasallowed to stir at ambient temperature for 72 hours. The reactionmixture was concentrated under reduced pressure and 10 mL of H₂O wasadded. The resulting solids were isolated by filtration, washed with 5mL of H₂O and twice with 5 mL of ethyl acetate, and dried to afford thetitle compound. MS (DCI/NH₃) m/z 303 (M+H)⁺.

Example 242B5-chloro-N-[(2Z)-5-chloro-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

To a slurry of sodium hydride (40 mg of a 60% dispersion, 1.0 mmol) in 4mL of N,N-dimethylformamide at 0° C. was added Example 242A (0.20 g,0.66 mmol). This mixture was allowed to warm to ambient temperature andstirred for 1 hour. The mixture was cooled to 0° C. and Example 208A(0.19 g, 0.73 mmol) was added. The mixture was warmed to 80° C. andallowed to stir for 24 hours and cooled to ambient temperature. Thereaction mixture was quenched with ice and 5 mL of saturated, aqueousNH₄Cl and diluted with 5 mL of ethyl acetate. The layers were separatedand the aqueous layer was extracted with three 5 mL of portions of ethylacetate. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. Purification via flashcolumn chromatography (SiO₂, 50% hexanes:ethyl acetate) afforded thetitle compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.65-1.80 (m, 1H),1.85-1.97 (m, 2H), 2.02-2.18 (m, 1H), 3.72-3.82 (m, 1H), 3.84-3.94 (m,1H), 3.87 (s, 3H), 4.21-4.38 (m, 2H), 4.40-4.48 (m, 1H), 7.09 (d, J=8.8Hz, 1H), 7.43 (dd, J=9.0, 2.9 Hz, 1H), 7.50 (s, 1H), 7.90 (d, J=2.7 Hz,1H); MS (DCI/NH₃) m/z 387 (M+H)⁺. Anal. Calculated for C₁₆H₁₆Cl₂N₂O₃S:C, 49.62; H, 4.16; N, 7.23. Found: C, 50.49; H, 4.03; N, 6.70.

Example 2435-chloro-N-[(2Z)-5-chloro-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 242A (0.20 g, 0.66 mmol), Example 203A (0.20, 0.73 mmol) and NaH(40 mg, 1 mmol) in 4 mL of tetrahydrofuran and 1 mL ofN,N-dimethylformamide were processed as in Example 242B to afford thetitle compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.36-1.52 (m, 2H),1.53-1.61 (m, 2H), 2.19-2.38 (m, 1H), 3.40 (dt, J=11.7, 2.4 Hz, 2H),3.88 (s, 3H), 3.92-4.00 (m, 2H), 4.19 (d, J=7.1 Hz, 2H), 7.10 (d, J=8.8Hz, 1H), 7.44 (dd, J=9.0, 2.9 Hz, 1H), 7.55 (s, 1H), 7.91 (d, J=2.7 Hz,1H); MS (DCI/NH₃) m/z 401 (M+H)⁺.

Example 244N-[(2Z)-5-tert-butyl-3-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 244A N-(5-tert-butylthiazol-2-yl)-5-chloro-2-methoxybenzamide

To a solution of Example 202A (0.94 g, 6.0 mmol) in tetrahydrofuran (40mL) was added Example 205B (1.23 g, 6.0 mmol), triethylamine (2.4 mL, 18mmol), and 4-dimethylaminopyridine (7.5 mg, 0.06 mmol). The reactionmixture was stirred at 60° C. for 14 hours and then cooled to ambienttemperature, diluted with saturated aqueous NaHCO₃ (20 mL) and extractedwith ethyl acetate (3×30 mL). The combined organic extracts were driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was purified by column chromatography using an Analogix®Intelliflash280™ (SiO₂, 0-100% ethyl acetate in hexanes) to afford thetitle compound. MS (ESI⁺) m/z 325 (M+H)⁺

Example 244BN-[(2Z)-3-allyl-5-tert-butyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

To a solution of Example 244A (410 mg, 1.3 mmol) in 5 mL oftetrahydrofuran:N,N-dimethylformamide (4/1) at 0° C. was added potassiumtert-butoxide (230 mg, 1.9 mmol). The reaction mixture was stirred for 1hour then allyl bromide (0.16 mL, 1.9 mmol) was added. The mixture waswarmed to 65° C. and stirred overnight. The mixture was cooled toambient temperature, concentrated, diluted with CH₂Cl₂ and washed withwater and brine. The organic layer was dried over magnesium sulfate,filtered, and concentrated under reduced pressure. Purification bychromatography (20-50% ethyl ccetate/hexane gradient) afforded the titlecompound. ¹H NMR (CDCl₃, 300 MHz) δ ppm 1.34 (s, 9H), 3.90 (s, 3H),4.78-4.85 (m, 3H), 5.22-5.36 (m, 2H), 5.90-6.09 (m, J=17.0, 10.17 Hz,1H), 6.62 (s, 1H), 6.90 (d, J=9.2 Hz, 1H), 7.32 (dd, J=8.8, 3.1 Hz, 1H),8.00 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 365 (M+H)⁺.

Example 244CN-[(2Z)-5-tert-butyl-3-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244B was processed according to the method of Example 227C toafford the title compound. MS (DCI/NH₃) m/z 422 (M+H)⁺.

Example 245N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2,2-dimethyl-4-oxo-3,4-dihydro-2H-pyran-6-carboxamide

To a solution of the product from Example 240C (300 mg, 0.94 mmol) and2,2-dimethyl-4-oxo-3,4-dihydro-2H-pyran-6-carboxylic acid (180 mg, 1.0mmol) in 5 mL of N,N-dimethylformamide were added 1-hydroxybenzotriazolehydrate (190 mg, 1.4 mmol), triethylamine (0.30 mL, 2.1 mmol), and1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (260 mg,1.4 mmol). The mixture was warmed to 65° C. and stirred overnight. Themixture was cooled to ambient temperature, diluted with CH₂Cl₂ andwashed with water and brine. The organic extract was dried (MgSO₄),filtered, and concentrated under reduced pressure. Purification bycolumn chromatography (SiO₂, 20-40% ethyl acetate/hexanes gradient)afforded the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.34 (s, 9H),1.57 (s, 6H), 1.72-1.84, (m, 1H), 1.83-1.94 (m, 1H), 2.00-2.12 (m, 2H),2.55 (s, 2H), 3.73-3.88 (m, 2H), 4.10-4.27 (m, 2H), 4.39 (dd, J=13.7,2.8 Hz, 1H), 6.48 (s, 1H), 6.91 (s, 1H); MS (DCI/NH₃) m/z 393 (M+H)⁺.

Example 246N-[(2Z)-5-tert-butyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

To a solution of Example 244A (1.0 g, 3.1 mmol) in 4:1N,N-dimethylformamide/tetrahydrofuran (20 mL) were added potassiumtert-butoxide (Aldrich, 0.42 g, 3.7 mmol) and4-(iodomethyl)tetrahydro-2H-pyran (Maybridge, 0.97 g, 4.3 mmol). Thereaction mixture was stirred at 80° C. for 16 hours, cooled to roomtemperature, quenched with saturated aqueous NaHCO₃ (20 mL) andextracted with ethyl acetate (3×20 mL). The combined organic extractswere dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatographyusing an Analogix® Intelliflash280™ (SiO₂, 0-100% ethyl acetate inhexanes) to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.21-1.51 (m, 4H), 1.32 (s, 9H), 2.06-2.35(m, 1H), 3.20-3.30 (m, 2H), 3.79 (s, 3H), 3.80-3.91 (m, J=9.3, 2.2, 2.0Hz, 2H), 4.06 (d, J=7.1 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.30 (s, 1H),7.45 (dd, J=8.8, 3.1 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H); MS (ESI⁺) m/z 423(M+H)⁺; Anal. Calculated for C₂₁H₂₇ClN₂O₃S: C, 59.63; H, 6.43; N, 6.62.Found: C, 59.66; H, 6.36; N, 6.56.

Example 2475-chloro-2-methoxy-N-[(2Z)-3-(tetrahydro-2H-pyran-4-ylmethyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-2(3H)-ylidene]benzamideExample 247A5-chloro-2-methoxy-N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzamide

Commercially available 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine(Aldrich) and 5-chloro-2-methoxybenzoic acid (Aldrich) were processedusing the method described in Example 58 to afford the title compound.MS (ESI⁺) m/z 323 (M+H)⁺

Example 247B5-chloro-2-methoxy-N-[(2Z)-3-(tetrahydro-2H-pyran-4-ylmethyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-2(3H)-ylidene]benzamide

Example 203A and Example 247A were processed using the method describedin Example 246 to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.25-1.55 (m, 4H), 1.69-1.94 (m, 4H),2.07-2.30 (m, 1H), 2.52-2.59 (m, 2H), 2.58-2.66 (m, 2H), 3.18-3.30 (m,2H), 3.80 (s, 3H), 3.81-3.89 (m, 2H), 4.03 (d, J=7.1 Hz, 2H), 7.11 (d,J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.7 Hz, 1H), 7.69 (d, J=3.1 Hz, 1H); MS(ESI⁺) m/z 421 (M+H)⁺.

Example 2485-chloro-2-methoxy-N-[(2Z)-3-(2-methoxyethyl)-4,4,6,6-tetramethyl-4,6-dihydrofuro[3,4-d]-[1,3]thiazol-2(3H)-ylidene]benzamideExample 248A 4-bromo-2,2,5,5-tetramethyldihydrofuran-3(2H)-one

To a solution of commercially available2,2,5,5-tetramethyldihydrofuran-3(2H)-one (Aldrich, 10.0 g, 0.07 mol) inCH₂Cl₂ (100 mL) was added bromine (Aldrich, 3.6 mL, 0.07 mol,) dropwiseat room temperature. The reaction mixture was stirred for 2 hours overwhich time the reaction mixture became clear. Then, the reaction mixturewas cooled to 0° C., quenched with NaHCO₃ powder in small portions,filtered and concentrated under reduced pressure to afford the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.26 (s, 3H),1.27 (s, 3H), 1.30 (s, 3H), 1.39 (s, 3H), 5.22 (s, 1H).

Example 248B 4,4,6,6-tetramethyl-4,6-dihydrofuro[3,4-d]thiazol-2-amine

To a solution of Example 248A (10.0 g, 0.045 mol) in ethanol (100 mL)were added thiourea (3.8 g, 0.05 mol) and triethylamine (6.3 mL, 0.045mol). The reaction mixture was heated at reflux overnight, then cooled,and concentrated under reduced pressure. The residue was diluted withwater (25 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by column chromatography (SiO₂, 0-5% methanol inCH₂Cl₂) to afford the title compound. MS (ESI⁺) m/z 199 (M+H)⁺.

Example 248C5-chloro-2-methoxy-N-(4,4,6,6-tetramethyl-4,6-dihydrofuro[3,4-d]thiazol-2-yl)benzamide

Example 248B and Example 205B were processed using the method describedin Example 244A to afford the title compound. MS (ESI⁺) m/z 367 (M+H)⁺.

Example 248D5-chloro-2-methoxy-N-[(2Z)-3-(2-methoxyethyl)-4,4,6,6-tetramethyl-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]benzamide

Example 248C and commercially available 2-bromoethyl methyl ether(Aldrich) were processed using the method described in Example 246 toafford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm1.48 (s, 6H), 1.55 (s, 6H), 3.25 (s, 3H), 3.71-3.81 (s, 3H), 4.20 (t,J=5.6 Hz, 2H), 7.13 (d, J=9.2 Hz, 1H), 7.48 (dd, J=9.0, 2.9 Hz, 1H),7.68 (d, J=2.7 Hz, 1H); MS (ESI⁻) m/z 425 (M+H)⁺

Example 2495-chloro-2-methoxy-N-[(2Z)-3-(2-methoxyethyl)-6,6-dimethyl-4-oxo-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]benzamideExample 249A tert-butyl6,6-dimethyl-4-oxo-4,6-dihydrofuro[3,4-d]thiazol-2-ylcarbamate

To a solution of diisopropylamine (23.5 mL, 165 mmol) in tetrahydrofuran(200 mL) was added butyllithium (103 mL, 1.6 M in hexanes, 165 mmol)dropwise at −78° C. The solution was stirred at −78° C. for 30 minutesthen transferred via cannula into a solution of methyl2-(tert-butoxycarbonylamino)thiazole-4-carboxylate (Combi-Blocks, 14.2g, 55 mmol) in tetrahydrofuran (300 mL) at −78° C. After stirring at−78° C. for 30 minutes, dry acetone (Acros, 16.2 mL, 220 mmol) was addeddropwise and the reaction mixture was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was quenchedwith saturated aqueous NH₄Cl solution (200 mL) and the aqueous layer wasextracted with ethyl acetate (4×200 mL). The combined organic extractswere dried (Na₂SO₄), filtered and concentrated. The residue was purifiedby column chromatography (SiO₂, 0-100% ethyl acetate in hexanes) toafford the title compound. MS (ESI⁺) m/z 285 (M+H)⁺.

Example 249B 2-amino-6,6-dimethylfuro[3,4-d]thiazol-4(6H)-one

To a solution of Example 249A (7.4 g, 26.0 mmol) in CH₂Cl₂ (20 mL) wasadded trifluoroacetic acid (20.0 mL, 260 mmol) slowly at 0° C. Thereaction mixture was stirred at room temperature for 3 hours, and thenconcentrated under vacuum. The residue was diluted with ethyl acetate(100 mL) and neutralized with saturated aqueous NaHCO₃ solution. Thelayers were separated and the aqueous phase was extracted with ethylacetate (5×100 mL). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated to afford the title compound. MS (ESI⁺) m/z185 (M+H)⁺

Example 249C2-imino-3-(2-methoxyethyl)-6,6-dimethyl-2,3-dihydrofuro[3,4-d]thiazol-4(6H)-onehydrobromide

A mixture of Example 249B and commercially available 2-bromoethyl methylether (Aldrich) was processed at 120° C. using the method described inExample 12A to afford the title compound. MS (ESI⁺) m/z 243 (M+H)⁺

Example 249D5-chloro-2-methoxy-N-[(2Z)-3-(2-methoxyethyl)-6,6-dimethyl-4-oxo-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]benzamide

Example 249C and Example 205B were processed using the method describedin Example 244A to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.71 (s, 6H), 3.26 (s, 3H), 3.78 (t, J=5.6Hz, 2H), 3.82 (s, 3H), 4.46 (t, J=5.6 Hz, 2H), 7.17 (d, J=8.8 Hz, 1H),7.53 (dd, J=9.0, 2.9 Hz, 1H), 7.77 (d, J=2.7 Hz, 1H)); MS (ESI⁺) m/z 411(M+H)⁺; Anal. Calculated for C₁₈H₁₉ClN₂O₅S: C, 52.62; H, 4.66; N, 6.82.Found: C, 52.72; H, 4.49; N, 6.90.

Example 250N-[(2Z)-5-acetyl-4-methyl-3-(oxetan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 238A and Example 211A were processed using the method describedin Example 246 to afford the title compound. ¹H NMR (300 MHz, CDCl₃) δppm 2.49 (s, 3H), 2.54-2.67 (m, 1H), 2.74-2.82 (m, 1H), 2.84 (s, 3H),3.93 (s, 3H), 4.45-4.74 (m, 4H), 5.30 (d, 1H), 6.93 (d, J=9.2 Hz, 1H),7.38 (dd, J=8.8, 2.7 Hz, 1H), 7.97 (d, J=2.7 Hz, 1H); MS (ESI⁺) m/z 493(M+H)⁺; Anal. Calculated for C₁₈H₁₉ClN₂O₄S: C, 54.75; H, 4.85; N, 7.09.Found: C, 54.68; H, 4.70; N, 7.07.

Example 2515-chloro-N-[(2Z)-4,4-dimethyl-1-(oxetan-2-ylmethyl)-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]-2-methoxybenzamideExample 251A ethyl 2-(2-(tert-butoxycarbonylamino)thiazol-4-yl)acetate

The title compound was obtained from commercially available ethyl2-(2-aminothiazol-4-yl)acetate (Aldrich) as per the procedure describedin JP 06345736. MS (ESI⁺) m/z 287 (M+H)⁺.

Example 251B tert-butyl 4-(2-hydroxyethyl)thiazol-2-ylcarbamate

To a cooled solution of Example 251A in tetrahydrofuran (100 mL) wasadded lithium borohydride (Aldrich, 100 mL, 2 M solution intetrahydrofuran) at 0° C. The reaction mixture was heated at refluxovernight, then cooled to 0° C., quenched with water and extracted withethyl acetate (3×100 mL). The combined organic extracts were dried(Na₂SO₄), filtered and concentrated. The residue was purified by columnchromatography (SiO₂, 0-5% methanol in CH₂Cl₂) to afford the titlecompound. MS (ESI⁺) m/z 245 (M+H)⁺

Example 251C tert-butyl4-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)thiazol-2-ylcarbamate

To a solution of Example 251B (6.3 g, 27.4 mmol) in CH₂Cl₂ (100 mL) wasadded commercially available 3,4-dihydro-2H-pyran (Aldrich, 21 g, 250mmol) and pyridinium-p-toluenesulfonic acid (Aldrich, 3.5 g, 14.0 mmol).The reaction mixture was stirred overnight at room temperature and wasdiluted with CH₂Cl₂, washed with water, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by column chromatography (SiO₂,0-100% ethyl acetate in hexanes) to afford the title compound. MS (ESI⁺)m/z 329 (M+H)⁺

Example 251D tert-butyl5-(2-hydroxypropan-2-yl)-4-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)thiazol-2-ylcarbamate

Example 251C, diisopropylamine, butyllithium, and dry acetone (Acros)were processed as described for Example 249A to obtain the titlecompound. MS (ESI⁺) m/z 387 (M+H)⁺.

Example 251E 4,4-dimethyl-6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-amine

To a solution of Example 251D (4.6 g, 11 mmol) in tetrahydrofuran wasadded concentrated HCl (6.9 mL). The reaction mixture was heated atreflux for overnight and then cooled. The mixture was basified with 5NNaOH (17 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by column chromatography (SiO₂, 0-10% methanol inCH₂Cl₂) to afford the title compound. MS (ESI⁺) m/z 185 (M+H)⁺.

Example 251F5-chloro-N-(4,4-dimethyl-6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2-methoxybenzamide

Example 251E and Example 205B were processed using the method describedin Example 244A to afford the title compound. MS (ESI⁺) m/z 353 (M+H)⁺

Example 251G5-chloro-N-[(2Z)-4,4-dimethyl-1-(oxetan-2-ylmethyl)-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]-2-methoxybenzamide

Example 251F and Example 211A were processed using the method describedin Example 246 to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.45 (s, 3H), 1.46 (s, 3H), 2.67-2.75 (m,2H), 2.74-2.83 (m, 2H), 3.79 (s, 3H), 3.90-4.01 (m, 2H), 4.32-4.44 (m,2H), 4.45-4.58 (m, 2H), 5.06 (d, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.45 (dd,J=8.8, 2.7 Hz, 1H), 7.62 (d, J=2.7 Hz, 1H); MS (ESI⁺) m/z 423 (M+H)⁺;Anal. Calculated for C₂₀H₂₃ClN₂O₄S.0.2C₄H₈O₂: C, 56.71; H, 5.63; N,6.36. Found: C, 56.33; H, 5.39; N, 6.41.

Example 2525-chloro-N-{(2Z)-4,4-dimethyl-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene}-2-methoxybenzamide

Example 251F and Example 208A were processed using the method describedin Example 246 to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.45 (s, 6H), 1.61-2.04 (m, 4H), 2.71 (t,J=5.8 Hz, 2H), 3.56-3.70 (m, 1H), 3.73-3.84 (m, 1H), 3.79 (s, 3H), 3.96(t, J=5.3 Hz, 2H), 4.00-4.05 (m, 1H), 4.20-4.38 (m, 2H), 7.11 (d, J=8.8Hz, 1H), 7.46 (dd, J=9.0, 2.9 Hz, 1H), 7.66 (d, J=3.1 Hz, 1H); MS (ESI⁺)m/z 437 (M+H)⁺; Anal. Calculated for C₂₁H₂₅ClN₂O₄S: C, 57.72; H, 5.77;N, 6.41. Found: C, 57.58; H, 5.86; N, 6.33.

Example 253N-[(2Z)-5-acetyl-4-methyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Commercially available 2-(bromomethyl)tetrahydro-2H-pyran (Aldrich) andExample 238A were processed using the method described in Example 246 toafford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm1.28-1.38 (m, 1H), 1.41-1.52 (m, 3H), 1.62-1.71 (m, 1H), 1.78-1.88 (m,1H), 2.50 (s, 3H), 2.61-2.84 (m, 3H), 3.64-3.93 (m, 3H), 3.83 (s, 3H),4.14 (dd, J=14.1, 8.6 Hz, 1H), 4.37 (dd, J=14.2, 3.1 Hz, 1H), 7.16 (d,J=8.8 Hz, 1H), 7.51 (dd, J=9.0, 2.9 Hz, 1H), 7.79 (d, J=2.7 Hz, 1H); MS(ESI⁺) m/z 423 (M+H)⁺; Anal. Calculated for C₂₀H₂₃ClN₂O₄S: C, 56.80; H,5.48; N, 6.62. Found: C, 56.53; H, 5.27; N, 6.55.

Example 254N-[(2Z)-5-acetyl-4-methyl-3-(tetrahydro-2H-pyran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 225A and Example 238A were processed using the method describedin Example 246 to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.47 (s, 6H) 1.52 (s, 6H) 3.72 (s, 3H) 5.35(s, 2H) 7.07 (d, 3H) 7.32 (d, 1H) 7.37 (d, J=2.71 Hz, 1H) 7.40-7.50 (m,J=8.81 Hz, 1H); MS (ESI⁺) m/z 423 (M+H)⁺; Anal. Calculated forC₂₀H₂₃ClN₂O₄S.0.2H₂O: C, 56.32; H, 5.53; N, 6.57. Found: C, 56.19; H,5.50; N, 6.62.

Example 2555-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

A solution of methyllithium (Aldrich, 1.6 M in diethyl ether, 0.41 mL,0.66 mmol) was added slowly a solution of Example 253 (0.14 g, 0.33mmol) in tetrahydrofuran (3 mL) at −78° C. The reaction mixture wasstirred at −78° C. for 30 minutes and was allowed to reach roomtemperature. The reaction mixture was quenched with water (6 mL) andextracted with ethyl acetate (2×10 mL). The combined organic extractswere dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatographyusing an Analogix® Intelliflash280™ (SiO₂, 0-5% methanol in CH₂Cl₂) toafford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm1.21-1.36 (m, 1H), 1.41-1.48 (m, 3H), 1.49 (s, 3H), 1.50 (s, 3H),1.57-1.67 (m, 1H), 1.74-1.85 (m, 1H), 2.42 (s, 3H), 3.68-3.89 (m, 3H),3.79 (s, 3H), 3.92-4.09 (m, 1H), 4.17-4.38 (m, 1H), 5.60 (s, 1H), 7.10(d, J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 2.7 Hz, 1H), 7.68 (d, J=2.7 Hz, 1H);MS (ESI⁺) m/z 439 (M+H)⁻; Anal. Calculated for C₂₁H₂₇ClN₂O₄S: C, 57.46;H, 6.20; N, 6.38. Found: C, 57.44; H, 5.88; N, 6.06.

Example 2565-chloro-2-methoxy-N-[(2Z)-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 256A2-(2-amino-4-methylthiazol-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

The title compound was prepared from commercially available of4-methylthiazol-2-amine (Aldrich) and hexafluoroacetone trihydrate(Aldrich) using the procedure described in European Journal of OrganicChemistry, (21), 4286-4291; 2003. MS (ESI⁺) m/z 281 (M+H)⁺.

Example 256B5-chloro-N-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4-methylthiazol-2-yl)-2-methoxybenzamide

Commercially available 5-chloro-2-methoxybenzoic acid (Aldrich) andExample 256A were processed using the method described in Example 58 toafford the title compound. MS (ESI⁺) m/z 449 (M+H)⁺.

Example 256C5-chloro-2-methoxy-N-[(2Z)-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3-thiazol-2(3H)-ylidene]benzamide

Example 256B and Example 208A were processed using the method describedin Example 246 to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.62-1.76 (m, 1), 1.78-1.93 (m, 2H),1.93-2.09 (m, 1H), 2.57 (s, 3H), 3.57-3.70 (m, 1H), 3.74-3.88 (m, 1H),3.80 (s, 3H), 4.12-4.26 (m, 1H), 4.39 (d, 2H), 7.14 (d, J=8.8 Hz, 1H),7.49 (dd, J=8.8, 2.7 Hz, 1H), 7.74 (d, J=2.7 Hz, 1H), 9.34 (s, 1H); MS(ESI⁺) m/z 533 (M+H)⁺.

Example 2575-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-(tetrahydro-2H-pyran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 254 and commercially available methyllithium (Aldrich, 1.6 M indiethyl ether) were processed using the method described in Example 255to afford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δppm 1.32-1.48 (m, 2H), 1.51 (s, 6H), 1.57-1.80 (m, 2H), 2.02-2.23 (m,1H), 2.41 (s, 3H), 3.19-3.28 (m, 1H), 3.35-3.43 (m, 1H), 3.55-3.73 (m,2H), 3.79 (s, 3H), 3.95-4.29 (m, 2H), 5.60 (s, 1H), 7.10 (d, J=8.8 Hz,1H), 7.44 (dd, J=8.8, 3.1 Hz, 1H), 7.67 (d, J=2.7 Hz, 1H); MS (ESI⁺) m/z439 (M+H)⁺; Anal. Calculated for C₂₁H₂₇ClN₂O₄S: C, 57.46; H, 6.20; N,6.38. Found: C, 57.14; H, 6.23; N, 6.53.

Example 2585-chloro-N-[(2Z)-3-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 258A5-chloro-N-(5-(2-hydroxypropan-2-yl)-4-methylthiazol-2-yl)-2-methoxybenzamide

Example 238A and methyllithium (Aldrich, 1.6M in diethyl ether) wereprocessed using the method described in Example 255 to afford the titlecompound. MS (ESI⁺) m/z 341 (M+H)⁺.

Example 258B5-chloro-N-[(2Z)-3-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 258A and commercially available(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate(Aldrich) were processed using the method described in Example 246 toafford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm1.25 (s, 3H), 1.31 (s, 3H), 1.50 (s, 6H), 2.45 (s, 3H), 3.78 (s, 3H),3.84 (dd, J=8.8, 6.1 Hz, 1H), 4.04 (dd, J=8.5, 6.4 Hz, 1H), 4.18-4.29(m, 1H), 4.32-4.42 (m, 1H), 4.46-4.58 (m, 1H), 5.63 (s, 1H), 7.10 (d,J=8.8 Hz, 1), 7.43 (dd, J=8.8, 2.7 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H); MS(ESI⁺) m/z 455 (M+H)⁺; Anal. Calculated for C₂₁H₂₇ClN₂O₅S: C, 55.44; H,5.98; N, 6.16. Found: C, 55.34; H, 5.79; N, 6.21.

Example 2595-chloro-N-[(2Z)-6,6-dimethyl-4-oxo-3-[(2R)-tetrahydrofuran-2-ylmethyl]-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 259A5-chloro-N-(6,6-dimethyl-4-oxo-4,6-dihydrofuro[3,4-d]thiazol-2-yl)-2-methoxybenzamide

Example 249B, triethylamine, 4-dimethylaminopyridine, and Example 205Bwere processed as described for Example 244A to obtain the titlecompound. MS (ESI⁺) m/z 353 (M+H)⁺.

Example 259B5-chloro-N-[(2Z)-6,6-dimethyl-4-oxo-3-[(2R)-tetrahydrofuran-2-ylmethyl]-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 259A and Example 208A were processed using the method describedin Example 246 to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.71 (s, 6H), 1.73-2.05 (m, 4H), 3.60-3.69(m, 1H), 3.72-3.81 (m, 1H), 3.82 (s, 3H), 4.18-4.35 (m, 2H), 4.35-4.47(m, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.53 (dd, J=8.8, 2.7 Hz, 1H), 7.76 (d,J=2.7 Hz, 1H); MS (ESI⁺) m/z 437 (M+H)⁺; Anal. Calculated forC₂₀H₂₁ClN₂O₅S.0.4H₂O: C, 54.09; H, 4.95; N, 6.31. Found: C, 53.81; H,4.55; N, 5.99.

Example 2605-chloro-N-[(2Z)-3-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 258A and commercially available(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate(Aldrich) were processed using the method described in Example 246 toafford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm1.25 (s, 3H), 1.31 (s, 3H), 1.50 (s, 6H), 2.45 (s, 3H), 3.78 (s, 3H),3.84 (dd, J=8.5, 6.1 Hz, 1H), 4.04 (dd, J=8.8, 6.4 Hz, 1H), 4.14-4.30(m, 1H), 4.32-4.43 (m, 1H), 4.43-4.63 (m, 1H), 5.63 (s, 1H), 7.10 (d,J=9.2 Hz, 1H), 7.43 (dd, J=9.0, 2.9 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H); MS(ESI⁺) m/z 455 (M+H)⁺; Anal. Calculated for C₂₁H₂₇ClN₂O₅S: C, 55.44; H,5.98; N, 6.16. Found: C, 55.73; H, 6.07; N, 6.07.

Example 261N-[(2Z)-5-acetyl-3-(1,4-dioxan-2-ylmethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 238A and commercially available 2-(iodomethyl)-1,4-dioxane(Synchem) were processed using the method described in Example 246 toafford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm2.50 (s, 3H), 2.72 (s, 3H), 3.33-3.42 (m, 1H), 3.45-3.56 (m, 2H),3.59-3.77 (m, 2H), 3.78-3.87 (m, 1H), 3.83 (s, 3H), 4.00-4.11 (m, 1H),4.12-4.25 (m, 1H), 4.31-4.43 (m, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.52 (dd,J=8.8, 3.1 Hz, 1H), 7.79 (d, J=2.7 Hz, 1H); MS (ESI⁺) m/z 425 (M+H)⁺;Anal. Calculated for C₁₉H₂₁ClN₂O₅S: C, 53.71; H, 4.98; N, 6.59. Found:C, 53.32; H, 4.73; N, 6.59.

Example 2625-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-(oxetan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 258A and Example 211A were processed using the method describedin Example 246 to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.50 (s, 6H), 2.47 (s, 3H), 2.59-2.84 (m,1H), 3.78 (s, 3H), 4.25-4.64 (m, 5H), 5.00-5.19 (m, 1H), 5.63 (s, 1H),7.09 (d, J=9.2 Hz, 1H), 7.43 (dd, J=8.8, 3.1 Hz, 1H), 7.60 (d, J=2.7 Hz,1H); MS (ESI⁺) m/z 411 (M+H)⁺; Anal. Calculated for C₁₉H₂₃ClN₂O₄S: C,55.54; H, 5.64; N, 6.82. Found: C, 55.41; H, 5.51; N, 6.78.

Example 2635-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-(tetrahydrofuran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 258A and Example 162A were processed using the method describedin Example 246 to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.51 (s, 6H), 1.65-1.82 (m, 1H), 1.84-2.03(m, 1H), 2.43 (s, 3H), 2.68-2.89 (m, 1H), 3.48-3.71 (m, 3H), 3.78 (s,3H), 3.80-3.93 (m, 1H), 4.08-4.34 (m, 2H), 5.62 (s, 1H), 7.09 (d, J=8.8Hz, 1H), 7.43 (dd, J=8.8, 3.1 Hz, 1H), 7.65 (d, J=2.7 Hz, 1H); MS (ESI⁺)m/z 425 (M+H)⁺; Anal. Calculated for C₂₀H₂₅ClN₂O₄S: C, 56.53; H, 5.93;N, 6.59. Found: C, 56.35; H, 5.55; N, 6.56.

Example 2645-chloro-N-[(2Z)-3-(1,4-dioxan-2-ylmethyl)-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 258A and commercially available 2-(iodomethyl)-1,4-dioxane(Synchem) were processed using the method described in Example 246 toafford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm0.93 (t, J=7.46 Hz, 3H) 1.28-1.38 (m, 2H) 1.45 (s, 6H) 1.63-1.78 (m, 2H)2.69 (t, J=5.42 Hz, 2H) 3.79 (s, 3H) 3.97 (t, J=5.42 Hz, 2H) 4.07-4.17(m, 2H) 7.11 (d, J=8.81 Hz, 1H) 7.46 (dd, J=8.81, 2.71 Hz, 1H) 7.69 (d,J=2.71 Hz, 1H); LCMS (ESI⁺) m/z 441 (M+H)⁺; Anal. Calculated forC₂₀H₂₅ClN₂O₅S: C, 54.48; H, 5.71; N, 6.35. Found: C, 54.54; H, 5.38; N,6.43.

Example 265N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-3-methoxy-2-naphthamide

Commercially available 3-methoxy-2-naphthoic acid (Aldrich) and Example240C were processed using the method described in Example 240E to affordthe title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.32(s, 9H), 1.58-1.74 (m, 1H), 1.75-1.88 (m, 2H), 1.88-1.97 (m, 1H),3.60-3.71 (m, 1H), 3.74-3.85 (m, 1H), 3.88 (s, 3H), 4.15-4.26 (m, 2H),4.27-4.41 (m, 1H), 7.24 (s, 1H), 7.31-7.43 (m, 2H), 7.45-7.55 (m, 1H),7.86 (dd, J=13.6, 8.5 Hz, 2H), 8.12 (s, 1H); MS (ESI⁺) m/z 425 (M+H)⁺;Anal. Calculated for C₂₀H₂₃ClN₂O₄S.0.2C₄H₈O₂.0.2H₂O: C, 66.82; H, 6.78;N, 6.28. Found: C, 66.70; H, 6.65; N, 6.33.

Example 266N-[(2Z)-5-tert-butyl-3-[(3-methyloxetan-3-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

To a solution of Example 244A (0.75 g, 2.31 mmol) inN,N-dimethylformamide/tetrahydrofuran (1:4, 20 mL) were added potassiumtert-butoxide (0.39 g, 3.46 mmol), tetrabutylammonium iodide (0.09 mg,0.23 mmol) and commercially available 3-(chloromethyl)-3-methyloxetane(TCI, 0.28 g, 2.31 mmol). The reaction mixture was stirred at 80° C. for16 hours, cooled, diluted with ethyl acetate (20 mL) and quenched withsaturated aqueous NaHCO₃ (20 mL). The aqueous layer was extracted withethyl acetate (2×20 mL). The combined organic layers were washed withwater (1×25 mL). The combined organic extracts were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography using an Analogix®Intelliflash280™ (SiO₂, 0-100% ethyl acetate in hexanes) to afford thetitle compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.24 (s,3H), 1.33 (s, 9H), 3.77 (s, 3H), 4.19 (d, J=6.1 Hz, 2H), 4.38 (s, 2H),4.69 (d, J=6.1 Hz, 2H), 7.10 (d, J=9.2 Hz, 1H), 7.29 (s, 1H), 7.44 (dd,J=9.0, 2.9 Hz, 1H), 7.58 (d, J=2.7 Hz, 1H); MS (ESI⁺) m/z 409 (M+H)⁺;Anal. Calculated for C₂₀H₂₅ClN₂O₃S: C, 58.74; H, 6.16; N, 6.85. Found:C, 58.92; H, 6.04; N, 6.84.

Example 2675-chloro-2-methoxy-N-[(2Z)-3-(tetrahydrofuran-2-ylmethyl)-3,4,5,6-tetrahydro-2H-cyclopenta[d][1,3]thiazol-2-ylidene]benzamideExample 267A 5,6-dihydro-4H-cyclopenta[d]thiazol-2-amine

A mixture of 2-chlorocyclopentanone (5.0 g, 40 mmol) and thiourea (3.0g, 40 mmol) was heated at 70° C. for 3 hours. After cooling, the solidwas triturated with ethanol and collected by filtration to afford thetitle compound. MS (ESI) m/z 141 (M+H)⁺.

Example 267B

Example 267A and 5-chloro-2-methoxybenzoic acid were processed using themethod described in Example 223A to afford the title compound. MS (ESI)m/z 309 (M+H)⁺.

Example 267C5-chloro-2-methoxy-N-[(2Z)-3-(tetrahydrofuran-2-ylmethyl)-3,4,5,6-tetrahydro-2H-cyclopenta[d][1,3]thiazol-2-ylidene]benzamide

Example 267B (150 mg, 0.49 mmol) intetrahydrofuran/N,N-dimethylformamide (2:1)(10 mL) was treated with NaH(60%) (24 mg, 0.58 mmol). After 10 minutes,2-(bromomethyl)tetrahydrofuran (96 mg, 0.58 mmol) was added and themixture was heated at 95° C. for 12 hours. After cooling to ambienttemperature, the mixture was diluted with water, and extracted withethyl acetate. The organic extract was dried (Na₂SO₄), filtered andconcentrated. Purification by chromatography afforded the titlecompound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 1.62-1.73 (m, 1H)1.79-1.88 (m, 2H) 1.91-2.02 (m, 1H) 2.35-2.44 (m, 2H) 2.77-2.91 (m, 4H)3.64 (dd, J=14.7, 7.1 Hz, 1H) 3.74-3.81 (m, 1H) 3.79 (s, 3H) 4.00 (dd,J=13.5, 8.0 Hz, 1H) 4.23 (dd, J=13.5, 3.7 Hz, 1H) 4.26-4.33 (m, 1H) 7.11(d, J=8.9 Hz, 1H) 7.44 (dd, J=8.9, 2.8 Hz, 1H) 7.68 (d, J=2.8 Hz, 1H);MS (ESI) m/z 393 (M+H)⁻.

Example 2685-chloro-2-methoxy-N-[(2Z)-3-(tetrahydro-2H-pyran-4-ylmethyl)-3,4,5,6-tetrahydro-2H-cyclopenta[d][1,3]thiazol-2-ylidene]benzamide

Example 267B and 4-(bromomethyl)tetrahydro-2H-pyran were processed usingthe method described in Example 267C to afford the title compound. ¹HNMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 1.33 (ddd, J=24.7, 11.90, 4.3Hz, 2H) 1.40-1.54 (m, 2H) 1.83-1.86 (m, 1H) 2.15-2.26 (m, 1H) 2.36-2.45(m, 2H) 2.82 (dt, J=20.8, 6.7 Hz, 4H) 3.26 (td, J=11.9, 1.8 Hz, 1H) 3.80(s, 3H) 3.84 (dd, J=11.6, 2.4 Hz, 2H) 3.99 (d, J=7.3 Hz, 2H) 7.11 (d,J=8.9 Hz, 1H) 7.45 (dd, J=8.9, 2.8 Hz, 1H) 7.70 (d, J=2.8 Hz, 1H); MS(ESI) m/z 407 (M+H)⁺.

Example 269N-[(2Z)-4,5-dimethyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2,2-dimethyltetrahydro-2H-pyran-4-carboxamideExample 269A

A mixture of 4,5-dimethylthiazol-2-amine (Aldrich) and2,2-dimethyltetrahydro-2H-pyran-4-carboxylic acid (Chembridge BuildingBlock Library) were processed using the method described in Example 223Ato afford the title compound. MS (ESI) m/z 269 (M+H)⁺.

Example 269BN-[(2Z)-4,5-dimethyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2,2-dimethyltetrahydro-2H-pyran-4-carboxamide

Example 269A and 4-(bromomethyl)tetrahydro-2H-pyran were processed usingthe method described in Example 267C to afford the title compound. ¹HNMR (300 MHz, dimethylsulfoxide d₆) δ ppm 1.11-1.14 (m, 3H) 1.15-1.18(m, 3H) 1.30-1.43 (m, 4H) 1.43-1.56 (m, 2H) 1.68-1.80 (m, 2H) 2.14-2.18(m, 3H) 2.19-2.23 (m, 3H) 2.55-2.71 (m, 1H) 3.16-3.26 (m, 2H) 3.35-3.41(m, 1H) 3.60 (dd, J=11.9, 2.4 Hz, 1H) 3.63-3.68 (m, 1H) 3.79-3.83 (m,1H) 3.83-3.87 (m, 1H) 4.01-4.03 (m, 1H) 4.03-4.06 (m, 1H); MS (ESI) m/z376 (M+H)⁺.

Example 270N-[(2Z)-5-tert-butyl-3-(oxetan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and the product from Example 211A were processed using themethod described in Example 244B to afford the title compound. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.35 (s, 9H) 2.39-2.56 (m, 1H) 2.68-2.83 (m, 1H)3.86-3.90 (s, 3H) 4.34-4.38 (m, 1H) 4.37-4.43 (m, 1H) 4.55 (dd, J=14.1,5.8 Hz, 1H) 4.62-4.68 (m, 1H) 5.15-5.22 (m, 1H) 6.89 (d, J=8.9 Hz, 1H)6.93-6.94 (m, 1H) 7.31 (dd, J=8.9, 2.8 Hz, 1H) 7.89 (d, J=2.8 Hz, 1H);MS (ESI) m/z 395 (M+H)⁺.

Example 271N-[(2Z)-5-tert-butyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and 2-(bromomethyl)tetrahydro-2H-pyran were processed usingthe method described in Example 246 to afford the title compound. ¹H NMR(500 MHz, CDCl₃) δ ppm 1.20-1.34 (m, 2H) 1.34 (s, 9H) 1.51-1.55 (m, 2H)1.71 (dt, J=12.8, 1.8 Hz, 1H) 1.85-1.92 (m, 1H) 3.39 (td, J=14.3, 11.3,3.4 Hz, 1H) 3.70-3.77 (m, 1H) 3.90 (s, 3H) 3.94-4.00 (m, 2H) 4.40 (dd,J=14.0, 3.0 Hz, 1H) 6.78 (s, 1H) 6.90 (d, J=8.9 Hz, 1H) 7.32 (dd, J=8.9,2.8 Hz, 1H) 7.95 (d, J=2.8 Hz, 1H); MS (ESI) m/z 423 (M+H)⁺.

Example 272N-[(2Z)-5-tert-butyl-3-(1,4-dioxan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and 2-(iodomethyl)-1,4-dioxane were processed using themethod described in Example 246 to afford the title compound. ¹H NMR(500 MHz, CDCl₃) δ ppm 1.34 (s, 9H) 3.32 (dd, J=11.60, 10.1 Hz, 1H)3.52-3.62 (m, 1H) 3.68-3.76 (m, 2H) 3.80 (dd, J=11.0, 2.8 Hz, 1H)3.85-3.91 (m, 1H) 3.90 (s, 3H) 4.00-4.06 (m, 1H) 4.05 (dd, J=19.5, 6.71Hz, 1H) 4.33 (dd, J=10.7, 3.1 Hz, 1H) 6.74 (s, 1H) 6.90 (d, J=8.9 Hz,1H) 7.33 (dd, J=8.9, 2.8 Hz, 1H) 7.92 (d, J=2.8 Hz, 1H); MS (ESI) m/z425 (M+H)⁺.

Example 273N-[(2Z)-5-tert-butyl-3-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl4-methylbenzenesulfonate were processed using the method described inExample 246 to afford the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm1.34 (s, 9H) 1.36 (s, 3H) 1.37 (s, 3H) 3.76 (dd, J=8.9, 6.7 Hz, 1H) 3.90(s, 3H) 4.11 (dd, J=8.9, 6.4 Hz, 1H) 4.31-4.42 (m, 2H) 4.47-4.53 (m, 1H)6.80 (s, 1H) 6.90 (d, J=8.9 Hz, 1H) 7.32 (dd, J=8.9, 2.75 Hz, 1H) 7.90(d, J=3.1 Hz, 1H); MS (ESI) m/z 439 (M+H)⁺.

Example 274N-[(2Z)-5-tert-butyl-3-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl4-methylbenzenesulfonate were processed using the method described inExample 246 to afford the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm1.35 (s, 9H) 1.36 (s, 3H) 1.37 (s, 3H) 3.76 (dd, J=8.9, 6.71 Hz, 1H)3.90 (s, 3H) 4.11 (dd, J=8.9, 6.4 Hz, 1H) 4.33-4.43 (m, 2H) 4.48-4.54(m, 1H) 6.81 (s, 1H) 6.90 (d, J=8.9 Hz, 1H) 7.33 (dd, J=8.9, 2.8 Hz, 1H)7.89 (d, J=2.8 Hz, 1H); MS (ESI) m/z 439 (M+H)⁺.

Example 275N-[(2Z)-5-tert-butyl-3-(tetrahydrofuran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and the product from Example 162A were processed using themethod described in Example 246 to afford the title compound. ¹H NMR(500 MHz, CDCl₃) δ ppm 1.35 (s, 9H) 1.71-1.79 (m, 1H) 1.98-2.10 (m, 1H)2.90-3.02 (m, 1H) 3.64 (dd, J=9.15, 5.19 Hz, 1H) 3.76-3.83 (m, 2H) 3.90(s, 3H) 3.95-4.01 (m, 1H) 4.08 (dd, J=13.43, 7.93 Hz, 1H) 4.24 (dd,J=13.12, 7.32 Hz, 1H) 6.63 (s, 1H) 6.91 (d, J=8.85 Hz, 1H) 7.33 (dd,J=8.85, 3.05 Hz, 1H) 7.97 (d, J=3.05 Hz, 1H); MS (ESI) m/z 409 (M+H)⁺.

Example 276N-[(2Z)-5-tert-butyl-3-(tetrahydro-2H-pyran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and the product from Example 225A were processed using themethod described in Example 246 to afford the title compound. ¹H NMR(500 MHz, CDCl₃) δ ppm 1.34 (s, 9H) 1.39-1.48 (m, 1H) 1.56-1.67 (m, 1H)1.69-1.77 (m, 1H) 1.78-1.89 (m, 1H) 2.23-2.34 (m, 1H) 3.34 (dd, J=11.0,8.2 Hz, 1H) 3.53 (ddd, J=9.2, 3.1 Hz, 1H) 3.74-3.85 (m, 2H) 3.90 (s, 3H)4.04-4.16 (m, 2H) 6.60 (s, 1H) 6.90 (d, J=8.9 Hz, 1H) 7.33 (dd, J=8.9,2.75 Hz, 1H) 7.98 (d, J=2.8 Hz, 1H); MS (ESI) m/z 423 (M+H)⁺.

Example 277N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxotetrahydrofuran-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 277A (S)-(5-oxotetrahydrofuran-2-yl)methyl4-methylbenzenesulfonate

A mixture of (S)-5-(hydroxymethyl)dihydrofuran-2(3H)-one,para-toluenesulfonyl chloride and pyridine were processed using themethod described in Example 162A to afford the title compound. MS (ESI)m/z 288 (M+18)⁺.

Example 277BN-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxotetrahydrofuran-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and the product from Example 277A were processed using themethod described in Example 246 to afford the title compound. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.34 (s, 9H) 2.07-2.20 (m, 1H) 2.34-2.48 (m, 2H)2.49-2.61 (m, 1H) 3.90 (s, 3H) 4.39 (dd, J=14.4, 6.1 Hz, 1H) 4.55 (dd,J=14.4, 3.1 Hz, 1H) 4.92-5.01 (m, 1H) 6.75 (s, 1H) 6.92 (d, J=8.9 Hz,1H) 7.35 (dd, J=8.9, 2.8 Hz, 1H) 7.92 (d, J=2.8 Hz, 1H); MS (ESI) m/z423 (M+H)⁺.

Example 278N-[(2Z)-5-acetyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-1-benzofuran-5-carboxamideExample 278A (R)-1-((tetrahydrofuran-2-yl)methyl)thiourea

To a 0° C. solution of (R)-(tetrahydrofuran-2-yl)methanamine (5.0 g,49.5 mmol) and triethylamine (690 uL, 4.95 mmol) in tetrahydrofuran (100mL) was added carbon disulfide (5.65 g, 74.3 mmol). Stirring wascontinued for 0.5 hour followed by the dropwise addition of 30% hydrogenperoxide (5.6 g, 49.5 mmol) so that the temperature was maintained below40° C. The reaction mixture was poured into water, and extracted withethyl acetate. The organic extract was dried (Na₂SO₄), filtered andconcentrated to afford an oil. The residue was dissolved intetrahydrofuran, and treated with 7 N ammonia in methanol (14.3 mL, 100mmol). The precipitate was collected by filtration and washed with waterto afford the title compound.

Example 278B(R)-1-(2-imino-4-methyl-3-((tetrahydrofuran-2-yl)methyl)-2,3-dihydrothiazol-5-yl)ethanone

To a solution of pentane-2,4-dione (451 mg, 4.5 mmol) and the productfrom Example 278A (786 mg, 4.5 mmol) in tetrahydrofuran (5 mL) was addeda mixture of dimethylsulfoxide (0.64 mL, 9.0 mmol) and concentrated HCl(0.75 mL, 9.0 mmol). The reaction mixture was heated at 40° C. for 12hours. After cooling to ambient temperature, the mixture was dilutedwith ethyl acetate and washed with saturated aqueous NaHCO₃. The organicextract was dried (Na₂SO₄), filtered and concentrated to afford thetitle compound. MS (ESI) m/z 241 (M+H)⁺.

Example 278CN-[(2Z)-5-acetyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-1-benzofuran-5-carboxamide

Example 298B and benzofuran-5-carboxylic acid were processed using themethod described in Example 223A to afford the title compound. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.73-1.84 (m, 1H) 1.91-2.03 (m, 2H) 2.16-2.26 (m,1H) 2.50 (s, 3H) 2.81 (s, 3H) 3.75 (dd, J=14.12, 6.44 Hz, 1H) 3.90 (dd,J=14.1, 7.4 Hz, 1H) 4.16 (dd, J=13.8, 8.0 Hz, 1H) 4.41-4.51 (m, 1H) 4.71(dd, J=13.8, 3.4 Hz, 1H) 6.88 (s, 1H) 7.55 (d, J=8.6 Hz, 1H) 7.68 (t,J=2.2 Hz, 1H) 8.30 (dt, J=8.6, 1.5 Hz, 1H) 8.57-8.59 (m, 1H); MS (ESI)m/z 385 (M+H)⁺.

Example 279N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-1-benzofuran-5-carboxamide

Example 278C (300 mg, 0.78 mmol) in tetrahydrofuran (20 mL) was treatedwith a solution of methyllithium in diethyl ether (1.56 mL, 1.56 mmol)at −78° C. The reaction mixture was stirred at −78° C. for 4 hours andquenched with saturated aqueous NH₄Cl, warmed to ambient temperature andextracted with ethyl acetate. The organic extract was dried (Na₂SO₄),filtered and concentrated. Purification by reverse phase HPLC affordedthe title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.65 (s, 3H) 1.67 (s,3H) 1.74-1.84 (m, 1H) 1.89-2.00 (m, 2H) 1.99-2.02 (m, 1H) 2.12-2.22 (m,1H) 2.55 (s, 3H) 3.76 (dd, J=14.3, 7.6 Hz, 1H) 3.90 (dd, J=15.0, 6.7 Hz,1H) 4.06 (dd, J=13.7, 7.3 Hz, 1H) 4.40-4.49 (m, 1H) 4.64 (dd, J=14.0,3.7 Hz, 1H) 6.85 (dd, J=2.1, 0.9 Hz, 1H) 7.52 (d, J=8.5 Hz, 1H) 7.66 (d,J=2.1 Hz, 1H) 8.30 (dd, J=8.5, 1.5 Hz, 1H) 8.57 (d, J=1.5 Hz, 1H); MS(ESI) m/z 401 (M+H)⁺.

Example 280N-[(2Z)-5-acetyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(2,2,2-trifluoroethoxy)benzamideExample 280AN-((2Z)-5-acetyl-4-methyl-3-(((2R)-tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)-5-chloro-2-fluorobenzamide

Example 278B and 5-chloro-2-fluorobenzoic acid were processed using themethod described in Example 223A to afford the title compound. MS (ESI)m/z 397 (M+H)⁺.

Example 280BN-[(2Z)-5-acetyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(2,2,2-trifluoroethoxy)benzamide

To the solution of the product from Example 280A (360 mg, 0.91 mmol) intetrahydrofuran (4 mL) was added 2,2,2-trifluoroethanol (227 mg, 2.27mmol) and a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran(2.27 mL, 2.27 mmol). The reaction mixture was stirred at roomtemperature for 24 hours. The mixture was diluted with water, andextracted with ethyl acetate. The organic extract was dried (Na₂SO₄),filtered and concentrated. Purification by reverse phase HPLC affordedthe title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.64-1.75 (m, 1H)1.90-2.00 (m, 2H) 2.10-2.20 (m, 1H) 2.51 (s, 3H) 2.80 (s, 3H) 3.73 (dd,J=15.9, 7.3 Hz, 1H) 3.88 (dd, J=15.3, 6.7 Hz, 1H) 4.07 (dd, J=13.7, 8.2Hz, 1H) 4.33-4.41 (m, 1H) 4.47 (dd, J=16.8, 8.2 Hz, 2H) 4.62 (dd,J=13.7, 2.8 Hz, 1H) 7.03 (d, J=8.5 Hz, 1H) 7.39 (dd, J=8.5, 2.8 Hz, 1H)8.02 (d, J=2.8 Hz, 1H); MS (ESI) m/z 477 (M+H)⁺.

Example 281N-[(2Z)-5-tert-butyl-3-[(5-methyltetrahydrofuran-2-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 281A hex-5-en-2-ol

A solution of hex-5-en-2-one (10 g, 102 mmol) in ether (60 mL) wastreated with lithium aluminum hydride (4.0 g, 110 mmol) and the mixturewas stirred at room temperature for 1 hour. The reaction mixture wasquenched with saturated aqueous NH₄Cl, and extracted with ether. Theorganic extract was dried (Na₂SO₄), filtered and concentrated to affordthe title compound.

Example 281B 2-(bromomethyl)-5-methyltetrahydrofuran

A solution of the product from Example 281A (6.9 g, 69 mmol) in CH₂Cl₂(100 mL) was treated with N-bromosuccinimide (14.7, 83 mmol). Thereaction mixture was stirred at room temperature for 48 hours, pouredinto water, and extracted with CH₂Cl₂. The organic extract was dried(Na₂SO₄), filtered and concentrated to afford the title compound. MS(ESI) m/z 179 (M+H)⁺.

Example 281CN-[(2Z)-5-tert-butyl-3-[(5-methyltetrahydrofuran-2-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and the product from Example 281B were processed using themethod described in Example 246 to afford the title compound. ¹H NMR(500 MHz, CDCl₃) δ ppm 1.22 (d, J=6.1 Hz, 3H) 1.33-1.37 (m, 9H)1.46-1.54 (m, 2H) 1.67-1.76 (m, 1H) 1.91-2.00 (m, 1H) 3.90 (s, 3H)4.01-4.08 (m, 1H) 4.29-4.34 (m, 2H) 4.39-4.46 (m, 1H) 6.89-6.90 (m, 1H)6.90-6.91 (m, 1H) 7.32 (dd, J=8.5, 3.1 Hz, 1H) 7.94 (d, J=2.8 Hz, 1H);MS (ESI) m/z 423 (M+H)⁺.

Example 282N-[(2Z)-5-tert-butyl-3-[(5,5-dimethyltetrahydrofuran-2-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 282A 2-methylhex-5-en-2-ol

A 0° C. solution of hex-5-en-2-one (10 g, 102 mmol) in ether (200 mL)was treated dropwise with a 3.0 M solution of methylmagnesium iodide inether (102 mL, 306 mmol) over 20 minutes. The reaction mixture wasgradually warmed to room temperature, and stirred for 1 hour, quenchedwith water, and filtered through Celite (ether wash). The filtrate wasconcentrated and the resulting residue was distilled (27-30° C. at 5 mmHg) to afford the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.23 (s,6H) 1.54-1.62 (m, 2H) 2.11-2.19 (m, 2H) 4.96 (dq, J=11.29, 1.83, 1.22Hz, 1H) 5.05 (dq, J=17.39, 1.53 Hz, 1H) 5.80-5.91 (m, 1H).

Example 282B 5-(bromomethyl)-2,2-dimethyltetrahydrofuran

The product from 282A was processed using the method described inExample 281B to afford the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm1.23 (s, 3H) 1.29 (s, 3H) 1.73-1.82 (m, 2H) 1.81-1.91 (m, 1H) 2.10-2.22(m, 1H) 3.32 (dd, J=10.13, 7.06 Hz, 1H) 3.43 (dd, J=9.82, 4.60 Hz, 1H)4.16-4.27 (m, 1H).

Example 282CN-[(2Z)-5-tert-butyl-3-[(5,5-dimethyltetrahydrofuran-2-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and the product from Example 282B were processed using themethod described in Example 246 to afford the title compound. ¹H NMR(400 MHz, dimethylsulfoxide-d₆) δ ppm 1.13 (s, 3H) 1.17 (s, 3H) 1.31 (s,9H) 1.54-1.62 (m, 1H) 1.64-1.72 (m, 1H) 1.72-1.80 (m, 1H) 1.93-2.04 (m,1H) 3.78 (s, 3H) 4.12 (dd, J=15.34, 6.75 Hz, 1H) 4.29-4.39 (m, 2H) 7.10(d, J=8.59 Hz, 1H) 7.20 (s, 1H) 7.44 (dd, J=8.59, 2.76 Hz, 1H) 7.64 (d,J=2.76 Hz, 1H); MS (ESI) m/z 437 (M+H)⁺.

Example 283 N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(2-methoxyethoxy)benzamideExample 283A

Example 240C and 5-chloro-2-fluorobenzoic acid were processed using themethod described in Example 223A to afford the title compound. MS (ESI)m/z 397 (M+H)⁺.

Example 283B N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(2-methoxyethoxy)benzamide

Example 283A and 2-methoxyethanol were processed using the methoddescribed in Example 280B to afford the title compound. ¹H NMR (500 MHz,CDCl₃) δ ppm 1.36 (s, 9H) 1.62-1.71 (m, 1H) 1.74-1.83 (m, 1H) 1.84-1.93(m, 1H) 2.02-2.11 (m, 1H) 3.42 (s, 3H) 3.77 (m, 3H) 3.84 (dd, J=15.0,6.71 Hz, 1H) 4.21 (t, J=5.2 Hz, 2H) 4.22-4.31 (m, 2H) 4.43 (dd, J=10.4Hz, 1H) 6.90 (s, 1H) 6.97 (d, J=8.9 Hz, 1H) 7.30 (dd, J=8.5, 2.8 Hz, 1H)7.89 (d, J=2.8 Hz, 1H) MS (ESI) m/z 477 (M+H)⁺.

Example 284N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-6-chloroquinoline-8-carboxamide

Example 240C and 6-chloroquinoline-8-carboxylic acid were processedusing the method described in Example 223A to afford the title compound.¹H NMR (400 MHz, CDCl₃) δ ppm 1.38 (s, 9H) 1.63-1.74 (m, 1H) 1.74-1.83(m, 1H) 1.82-1.93 (m, 1H) 1.98-2.08 (m, 1H) 3.72-3.88 (m, 2H) 4.18-4.30(m, 2H) 4.40 (dd, J=13.2, 2.5 Hz, 1H) 6.90 (s, 1H) 7.40 (dd, J=8.3, 4.0Hz, 1H) 7.82 (d, J=2.5 Hz, 1H) 7.99 (d, J=2.2 Hz, 1H) 8.06 (dd, J=8.3,1.84 Hz, 1H) 9.02 (dd, J=4.3, 1.84 Hz, 1H); MS (ESI) m/z 430 (M+H)⁺.

Example 2855-chloro-2-methoxy-N-[(2Z)-5-(1-methylcyclopropyl)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamideExample 285A 2-(2-aminothiazol-5-yl)propan-2-ol

To a −78° C. solution of thiazol-2-amine (7.0 g, 69.9 mmol) intetrahydrofuran (200 mL) was added a 10.0 M solution of butyllithium inhexane (14 mL, 140 mmol). The mixture was stirred at −78° C. for 1 hourand chlorotrimethylsilane (15.2 g, 140 mmol) was added dropwise. Themixture was allowed to warm up to −40° C., cooled to −78° C. and a 10.0M solution of butyllithium in hexane (7.0, 70 mmol) was added. After 10minutes, propan-2-one (8.12 g, 140 mmol) was added and the mixture wasstirred for 12 hours. The reaction mixture was quenched with saturatedaqueous NH₄Cl and extracted with ether. The organic extract was dried(Na₂SO₄), filtered and concentrated. The residue was purified by columnchromatography using an Analogix® Intelliflash280™ (SiO₂, 0-100% ethylacetate in hexanes) to afford the title compound. ¹H NMR (500 MHz,CDCl₃) δ ppm 1.61 (s, 6H) 5.04-5.19 (brs, 2H) 6.89 (s, 1H); MS (ESI) m/z159 (M+H)⁺.

Example 285B(R)-5-(prop-1-en-2-yl)-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-imine

Example 285A and the product from Example 208A were processed using themethod described in Example 240C to afford the title compound. MS (ESI)m/z 225 (M+H)⁺.

Example 285C

(R,Z)-5-chloro-2-methoxy-N-(5-(prop-1-en-2-yl)-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)benzamide

Example 285B and the product from Example 205B were processed using themethod described in Example 223A to afford the title compound. MS (ESI)m/z 393 (M+H)⁺.

Example 285D5-chloro-2-methoxy-N-[(2Z)-5-(1-methylcylopropyl)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamide

A 20 mL vial was charged with 1 mL of CH₂Cl₂ and 1,2-dimethoxyethane(110 mg, 1.22 mmol). The solution was cooled to −10° C. and diethylzinc(151 mg, 1.22 mmol) was added. To this mixture was added dropwisediiodomethane (654 mg, 2.44 mmol). After the addition was complete, theresulting clear solution was stirred for 10 minutes at −10° C. Asolution of Example 285C (80 mg, 0.204 mmol) was added. The mixture wasallowed to warm to room temperature, stirred for 16 hours, thenconcentrated. Purification by reverse phase preparative HPLC on a WatersSymmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradientof 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8minutes (10 minutes run time) at a flow rate of 40 mL/minutes) affordedExample 285D and Example 286. Characterization for Example 285D: ¹H NMR(400 MHz, CDCl₃) δ ppm 0.97-1.02 (m, 2H) 1.02-1.08 (m, 2H) 1.50 (s, 3H)1.62-1.72 (m, 1H) 1.82-1.91 (m, 1H) 1.93-2.04 (m, 1H) 2.21-2.31 (m, 1H)3.72-3.86 (m, 2H) 4.04 (s, 3H) 4.29-4.39 (m, 1H) 4.48-4.61 (m, 1H)4.80-4.93 (m, 1H) 7.02 (d, J=9.2 Hz, 1H) 7.54 (dd, J=8.9, 2.8 Hz, 1H)7.53-7.55 (m, 1H) 8.04 (d, J=2.8 Hz, 1H); MS (ESI) m/z 407 (M+H)⁻.

Example 2865-chloro-N-[(2Z)-5-(1-hydroxy-3-iodo-1-methylpropyl)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

See Example 285D for experimental details ¹H NMR (500 MHz, CDCl₃) δ ppm1.61 (d, J=1.53 Hz, 3H) 1.63-1.72 (m, 1H) 1.79-1.96 (m, 2H) 2.03-2.14(m, 2H) 2.40-2.47 (m, 2H) 3.02-3.11 (m, 1H) 3.19 (dd, J=17.4, 9.2 Hz,1H) 3.78 (dd, J=15.0, 7.0 Hz, 1H) 3.83-3.89 (m, 1H) 3.91 (s, 3H)4.15-4.22 (m, 1H) 4.25-4.31 (m, 1H) 6.91 (d, J=8.9 Hz, 1H) 7.11 (d,J=5.5 Hz, 1H) 7.34 (dd, J=8.5, 3.1 Hz, 1H) 7.96 (d, J=2.8 Hz, 1H); MS(ESI) m/z 550 (M+H)⁺.

Example 287N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-[(1-methylcyclopropyl)methoxy]benzamide

The product from 283A and (1-methylcyclopropyl)methanol were processedusing the method described in Example 280B to afford the title compound.¹H NMR (500 MHz, CDCl₃) δ ppm 0.36 (t, J=4.8 Hz, 2H) 0.55 (t, J=4.6 Hz,2H) 1.22 (s, 3H) 1.36 (s, 9H) 1.61-1.70 (m, 1H) 1.74-1.83 (m, 1H)1.83-1.92 (m, 1H) 2.01-2.10 (m, 1H) 3.77 (dd, J=14.3, 7.6 Hz, 1H) 3.81(s, 2H) 3.84 (dd, J=15.9, 8.2 Hz, 1H) 4.21 (dd, J=13.4, 6.41 Hz, 1H)4.23-4.29 (m, 1H) 4.42 (dd, J=13.4, 2.4 Hz, 1H) 6.86 (d, J=9.5 Hz, 1H)6.87-6.88 (m, 1H) 7.26 (dd, J=7.9, 3.7 Hz, 1H) 7.81 (d, J=2.8 Hz, 1H);MS (ESI) m/z 463 (M+H)⁺.

Example 288N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-isopropoxybenzamide

Example 283A and propan-2-ol were processed using the method describedin Example 280B to afford the title compound. ¹H NMR (500 MHz, CDCl₃) δppm 1.35 (s, 9H) 1.35 (d, J=5.8 Hz, 6H) 1.63-1.71 (m, 1H) 1.75-1.82 (m,1H) 1.83-1.92 (m, 1H) 2.01-2.10 (m, 1H) 3.77 (dd, J=14.65, 7.32 Hz, 1H)3.85 (dd, J=14.7, 6.7 Hz, 1H) 4.20 (dd, J=13.7, 6.4 Hz, 1H) 4.24-4.30(m, 1H) 4.42 (dd, J=13.4, 2.8 Hz, 1H) 4.49-4.57 (m, 1H) 6.86 (s, 1H)6.89 (d, J=8.9 Hz, 1H) 7.26 (dd, J=8.9, 2.8 Hz, 1H) 7.84 (d, J=2.8 Hz,1H); MS (ESI) m/z 437 (M+H)⁺.

Example 289N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-ethoxybenzamide

Example 283A and ethanol were processed using the method described inExample 280B to afford the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm1.35 (s, 9H) 1.44 (t, J=7.02 Hz, 3H) 1.62-1.73 (m, 1H) 1.75-1.83 (m, 1H)1.84-1.92 (m, 1H) 2.01-2.11 (m, 1H) 3.77 (dd, J=13.7, 7.6 Hz, 1H) 3.84(dd, J=14.7, 6.7 Hz, 1H) 4.13 (dd, J=14.0, 7.2 Hz, 2H) 4.22 (dd, J=13.4,6.0 Hz, 1H) 4.25-4.31 (m, 1H) 4.41 (dd, J=13.4, 2.8 Hz, 1H) 6.86 (s, 1H)6.89 (d, J=8.9 Hz, 1H) 7.29 (dd, J=8.9, 2.8 Hz, 1H) 7.91 (d, J=2.8 Hz,1H); MS (ESI) m/z 423 (M+H)⁻.

Example 290N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(tetrahydrofuran-3-yloxy)benzamide

Example 283A and tetrahydrofuran-3-ol were processed using the methoddescribed in Example 280B to afford the title compound. ¹H NMR (500 MHz,CDCl₃) δ ppm ¹H NMR (500 MHz, CDCl₃) δ ppm 1.36 (s, 9H) 1.61-1.70 (m,1H) 1.76-1.83 (m, 1H) 1.84-1.93 (m, 1H) 2.03-2.10 (m, 1H) 2.11-2.25 (m,2H) 3.77 (dd, J=14.0, 7.3 Hz, 1H) 3.82-3.91 (m, 2H) 3.98 (dd, J=15.3,8.5 Hz, 1H) 4.02 (d, J=3.7 Hz, 2H) 4.20 (ddd, J=6.4, 1.5 Hz, 1H)4.23-4.30 (m, 1H) 4.41 (dd, J=13.7, 3.1 Hz, 1H) 4.88-5.00 (m, 1H) 6.83(dd, J=8.9, 0.6 Hz, 1H) 6.88 (d, J=0.9 Hz, 1H) 7.28 (dd, J=8.9, 2.75 Hz,1H) 7.87 (t, J=3.1 Hz, 1H); MS (ESI) m/z 423 (M+H)⁺.

Example 291N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-[(2-methoxyethyl)(methyl)amino]benzamide

A mixture of the product from Example 283A (120 mg, 0.3 mmol),2-methoxy-N-methylethanamine (54 mg, 0.6 mmol) and triethylamine (127ul, 0.91 mmol) in tetrahydrofuran (1 mL) was heated at 120° C. in amicrowave (CEM) for 2 hours. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic extract was dried(Na₂SO₄), filtered, and concentrated. Purification by reverse phasepreparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μmparticle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueoustrifluoroacetic acid over 8 minutes (10 minutes run time) at a flow rateof 40 mL/minutes) to afford the title compound afforded the titlecompound. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.36 (s, 9H) 1.62-1.71 (m, 1H)1.78-1.86 (m, 1H) 1.86-1.93 (m, 1H) 2.01-2.11 (m, 1H) 2.89 (s, 3H) 3.26(s, 3H) 3.29 (t, J=6.1 Hz, 2H) 3.54 (t, J=6.4 Hz, 2H) 3.78 (dd, J=14.7,7.3 Hz, 1H) 3.85 (dd, J=15.0, 8.2 Hz, 1H) 4.18 (dd, J=13.7, 6.4 Hz, 1H)4.23-4.30 (m, 1H) 4.40 (dd, J=13.7, 3.1 Hz, 1H) 6.85 (s, 1H) 6.92 (d,J=8.9 Hz, 1H) 7.20 (dd, J=8.9, 2.8 Hz, 1H) 7.67 (d, J=2.4 Hz, 1H); MS(ESI) m/z 466 (M+H)⁺.

Example 292N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(difluoromethoxy)benzamide

Example 240C and 5-chloro-2-(difluoromethoxy)benzoic acid were processedusing the method described in Example 223A to afford the title compound.¹H NMR (500 MHz, CDCl₃) δ ppm 1.36 (s, 9H) 1.60-1.69 (m, 1H) 1.76-1.84(m, 1H) 1.85-1.93 (m, 1H) 2.02-2.12 (m, 1H) 3.78 (dd, J=13.7, 7.3 Hz,1H) 3.85 (dd, J=15.0, 6.7 Hz, 1H) 4.20 (dd, J=13.4, 6.4 Hz, 1H)4.24-4.30 (m, 1H) 4.44 (dd, J=13.7, 2.8 Hz, 1H) 6.73 (t, J=6.3 Hz, 1H)6.91 (s, 1H) 7.17 (d, J=8.5 Hz, 1H) 7.38 (dd, J=8.5, 2.8 Hz, 1H) 8.05(d, J=2.8 Hz, 1H); MS (ESI) m/z 445 (M+H)⁺.

Example 293N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(trifluoromethoxy)benzamide

Example 240C and 5-chloro-2-(trifluoromethoxy)benzoic acid wereprocessed using the method described in Example 223A to afford the titlecompound. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.36 (s, 9H) 1.58-1.67 (m, 1H)1.75-1.83 (m, 1H) 1.84-1.93 (m, 1H) 2.01-2.11 (m, 1H) 3.77 (dd, J=13.7,6.4 Hz, 1H) 3.84 (dd, J=15.0, 6.7 Hz, 1H) 4.18 (dd, J=13.7, 6.7 Hz, 1H)4.22-4.29 (m, 1H) 4.46 (dd, J=13.7, 2.8 Hz, 1H) 6.91 (s, 1H) 7.23 (dd,J=8.5, 1.2 Hz, 1H) 7.40 (dd, J=8.9, 2.8 Hz, 1H) 8.06 (d, J=2.8 Hz, 1H);MS (ESI) m/z 463 (M+H)⁺.

Example 294N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(2,2,2-trifluoroethoxy)benzamide

The product from 283A and 2,2,2-trifluoroethanol were processed usingthe method described in Example 280B to afford the title compound. ¹HNMR (500 MHz, CDCl₃) δ ppm 1.37 (s, 9H) 1.60-1.69 (m, 1H) 1.76-1.84 (m,1H) 1.85-1.93 (m, 1H) 2.02-2.11 (m, 1H) 3.78 (dd, J=13.7, 7.3 Hz, 1H)3.85 (dd, J=15.0, 7.0 Hz, 1H) 4.21 (dd, J=13.4, 6.4 Hz, 1H) 4.24-4.29(m, 1H) 4.43 (dd, J=11.0, 2.8 Hz, 1H) 4.47 (dd, J=17.1, 8.5 Hz, 2H) 6.91(s, 1H) 7.01 (d, J=8.9 Hz, 1H) 7.33 (dd, J=8.5, 2.8 Hz, 1H) 7.99 (d,J=2.8 Hz, 1H); MS (ESI) m/z 477 (M+H)⁻.

Example 295N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-[3-(dimethylamino)propoxy]benzamide

The product from 283A and 3-(dimethylamino)propan-1-ol were processedusing the method described in Example 280B to afford the title compound.¹H NMR (500 MHz, CDCl₃) δ ppm 1.38 (s, 9H) 1.62-1.71 (m, 1H) 1.84-1.91(m, 1H) 1.91-1.98 (m, 1H) 2.09-2.19 (m, 1H) 2.29-2.36 (m, 2H) 3.04-3.09(m, J=4.9 Hz, 2H) 3.81 (dd, J=13.7, 6.4 Hz, 1H) 3.87 (dd, J=15.0, 7.0Hz, 1H) 4.25-4.34 (m, 4H) 4.51 (d, J=12.8 Hz, 1H) 6.93 (d, J=9.2 Hz, 1H)7.00-7.02 (m, 1H) 7.44 (dd, J=8.9, 2.9 Hz, 1H) 8.20 (d, J=2.8 Hz, 1H)10.35-10.51 (m, 1H); MS (ESI) m/z 480 (M+H)⁺.

Example 2965,6-dichloro-N-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]quinoline-8-carboxamide

A mixture of Example 186A (145 mg), 5,6-dichloroquinoline-8-carboxylicacid (99.65 mg) (Bailey J. Heterocycl. Chem. 1974, 11, 229),1-hydroxybenzotriazole hydrate (55 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (79 mg)and triethylamine (0.14 mL) in tetrahydrofuran (3 mL) was heated at 70°C. on a shaker overnight, cooled, quenched in saturated NaHCO₃ andextracted with ethyl acetate (2×). The organic extracts were dried(Na₂SO₄), filtered and the solvent was evaporated. The crude materialwas purified by reverse phase preparative HPLC on a Waters Symmetry C8column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to100% acetonitrile:10 mM ammonium acetate over 8 minutes (10 minutes runtime) at a flow rate of 40 mL/minutes) to afford the title compound. ¹HNMR (300 MHz, CDCl₃) δ ppm 1.62-1.75 (m, 1H), 1.85-1.95 (m, 2H), 2.0-2.1(m, 1H), 2.26 (s, 3H), 2.30 (s, 3H), 3.70-3.77 (m, 1H), 3.83-3.90 (m,1H), 3.97 (dd, 1H), 4.35-4.42 (m, 1H), 4.55 (dd, 1H), 7.53 (dd, 1H),8.60 (dd, 1H), 9.07 (m, 1H); MS (DCI/NH₃) m/z 436, 438 (M+H)⁺.

Example 2976-chloro-N-[(2Z)-4,5-dimethyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]quinoline-8-carboxamide

A mixture of Example 186A (106 mg), 6-chloro-quinoline-8-carboxylic acid(73 mg) (Weyer et al, Arzneim. Forsch 1974, 24, 269),1-hydroxybenzotriazole hydrate (47 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (69 mg),and triethylamine (0.15 mL) in tetrahydrofuran (2 mL) was heated to 70°C. on a shaker overnight, cooled, poured into saturated NaHCO₃ andextracted with ethyl acetate (2×). The organic extracts were dried(Na₂SO₄), filtered and the solvent was evaporated. The crude materialwas dissolved in warm methanol and allowed to cool overnight. The solidprecipitate was discarded, the filtrate was concentrated to dryness,triturated with cold methanol, and collected to afford the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.56-1.64 (m,1H), 1.70-1.95 (m, 3H), 2.26 (s, 3H), 2.27 (s, 3H), 3.57-3.65 (m, 1H),3.73-3.80 (m, 1H), 3.97-4.05 (m, 1H), 4.24-4.35 (m, 2H), 7.60 (dd, 1H),7.78 (d, 1H), 8.15 (d, 1H), 8.38 (dd, 1H), 8.91 (dd, 1H); MS (DCI/NH₃)m/z 402 (M+H)⁺.

Example 2986-chloro-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]quinoline-8-carboxamide

A mixture of Example 149A (142 mg), 6-chloro-quinoline-8-carboxylic acid(105 mg) (Weyer et al, Arzneim. Forsch 1974, 24, 269),1-hydroxybenzotriazole hydrate (67 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (94 mg),and triethylamine (0.15 mL) in tetrahydrofuran (3 mL) was heated to 70°C. for 24 hours, cooled, poured into saturated NaHCO₃ and extracted withethyl acetate (2×). The organic extracts were dried (Na₂SO₄), filteredand the solvent was evaporated. The crude material was purified byreverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile: 10mM ammonium acetate over 8 minutes (10 minutes run time) at a flow rateof 40 mL/minutes) to afford the title compound. ¹H NMR (300 MHz, CDCl₃)δ ppm 1.65-1.72 (m, 1H), 1.80-1.95 (m, 2H), 2.0-2.1 (m, 1H), 2.34 (d,J=1.4 Hz, 3H), 3.74-3.90 (m, 2H), 4.14 (dd, 1H), 4.2-4.3 (m, 1H), 4.47(dd, 1H), 6.95 (q, J=1.4 Hz, 1H), 7.42 (dd, 1H), 7.84 (d, 1H), 8.03 (d,1H), 8.08 (dd, 1H), 9.04 (dd, 1H); MS (DCI/NH₃) m/z 388 (M+H)⁺.

Example 2995,6-dichloro-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]quinoline-8-carboxamide

A mixture of Example 149A (117 mg), 5,6-dichloroquinoline-8-carboxylicacid (71 mg), 1-hydroxybenzotriazole hydrate (51 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (79 mg)and triethylamine (0.15 mL) in tetrahydrofuran was processed andpurified according to the method of Example 298 to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.6-1.71 (m, 1H), 1.78-1.95 (m,2H), 2.0-2.1 (m, 1H), 2.34 (d, J=1.4 Hz, 3H), 3.72-3.90 (m, 2H), 4.12(dd, 1H), 4.2-4.3 (m, 1H), 4.46 (dd, 1H), 6.94 (q, J=1.4 Hz, 1H), 7.53(dd, 1H), 8.60 (dd, 1H), 9.06 (dd, 1H); MS (DCI/NH₃) m/z 422 (M+H)⁺.

Example 3003-methoxy-N-[(2Z)-5-methyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-naphthamide

A mixture of Example 149A (113 mg), 3-methoxy-2-naphthoic acid (Aldrich)(69 mg), 1-hydroxybenzotriazole hydrate (50 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (79 mg)and triethylamine (0.15 mL) in tetrahydrofuran (2 mL) was shaken overthe weekend at room temperature, poured into saturated NaHCO₃ andextracted with ethyl acetate (2×). The organic extracts were dried(Na₂SO₄), filtered and the solvent was evaporated. The crude materialwas purified by flash chromatography over silica gel eluting with ethylacetate:hexane (7:3) to afford the title compound. ¹H NMR (300 MHz,CDCl₃) δ ppm 1.64-1.78 (m, 1H), 1.80-1.95 (m, 2H), 2.02-2.15 (m, 1H),2.32 (d, J=1.4 Hz, 3H), 3.74-3.92 (m, 2H), 4.01 (s, 3H), 4.2 (dd, 1H),4.27-4.35 (m, 1H), 4.51 (d, 1H), 6.91 (br s, 1H), 7.20 (s, 1H), 7.33 (m,1H), 7.46 (m, 1H), 7.73 (d, 1H), 7.81 (d, 1H), 8.42 (s, 1H); MS(DCI/NH₃) m/z 383 (M+H)⁻.

Example 301N-[(2Z)-5-tert-butyl-3-[(cis)-(3-methoxycyclobutyl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 301A cis-3-benzyloxymethylcyclobutanol methyl ether

To a solution of cis-3-benzyloxymethylcyclobutanol (Albany MolecularResearch Institute, 1.0 g, 5.2 mmol) in 10 mL of tetrahydrofuran at 0°C. was added NaH (0.62 g, 15.6 mmol). The mixture stirred for 15 minutesand iodomethane (0.49 mL, 7.8 mmol) was added and the mixture wasallowed to warm to ambient temperature and stirred for 16 hours. Somestarting material remained by TLC so additional NaH (0.21, 5.2 mmol) andiodomethane (0.32 mL, 5.2 mmol) were added and the mixture stirred foran additional 2 hours. The mixture was quenched with 10 mL of NH₄Cl anddiluted with 10 mL of ethyl acetate. The layers were separated and theaqueous layer was extracted twice with 5 mL portions of ethyl acetate.The combined organic extracts were dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. Purification via columnchromatography (SiO₂, 75% hexanes in ethyl acetate) afforded the titlecompound. MS (DCI/NH₃) m/z 207 (M+H)⁺.

Example 301B (cis-3-methoxycyclobutyl)methanol

A solution of Example 301A (1.05 g, 5.2 mmol) in 10 mL of ethanol wasdegassed and the flask was filled with N₂. This was repeated twoadditional times. Pd/C (0.1 g, 10 wt %) was added and the mixture wasdegassed again and flushed with N₂. This was repeated two additionaltimes and the flask was put under 1 atm. of H₂ and the mixture wasallowed to stir at ambient temperature for 72 hours. The mixture wasdegassed and the flask was filled with N₂. The reaction mixture wasfiltered, concentrated under reduced pressure and purified by columnchromatography (SiO₂, 25% hexanes in ethyl acetate) to afford the titlecompound. MS (DCI/NH₃) m/z 134 (M+NH₄)⁺.

Example 301C (cis-3-methoxycyclobutyl)methyl 4-methylbenzenesulfonate

Example 301B (0.49 g, 4.2 mmol) and p-toluenesulfonyl chloride (0.80 g,4.2 mmol) in 5 mL of CH₂Cl₂ and 5 mL of pyridine were processed as inExample 203A to afford the title compound. MS (DCI/NH₃) m/z 288(M+NH₄)⁺.

Example 301D5-tert-butyl-3-((cis-3-methoxycyclobutyl)methyl)thiazol-2(3H)-imine

Example 240A (0.25 g, 1.6 mmol), Example 301C (0.44 g, 1.6 mmol) andtetrabutylammonium iodide (0.30 g, 0.81 mmol) in 0.5 mL ofN,N-dimethylformamide were processed as in Example 240C to afford thetitle compound. MS (DCI/NH₃) m/z 266 (M+H)⁺.

Example 301EN-[(2Z)-5-tert-butyl-3-[(cis)-(3-methoxycyclobutyl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 301D (0.19 g, 0.75 mmol), triethylamine (0.31 mL, 2.2 mmol) andExample 205B (0.75 mmol) in 10 mL of tetrahydrofuran were processed asin Example 208D to afford the title compound (0.105 g, 0.25 mmol, 33%yield). ¹H NMR (300 MHz, CD₃OD) δ ppm 1.38 (s, 9H), 1.71-1.84 (m, 2H),2.31-2.47 (m, 3H), 3.21 (s, 3H), 3.71-3.83 (m, 1H), 3.86 (s, 3H), 4.29(d, J=6.4 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H), 7.14 (s, 1H), 7.40 (dd,J=8.8, 3.1 Hz, 1H), 7.83 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 423 (M+H)⁺.Anal. Calculated for C₂₁H₂₇ClN₂O₃S: C, 59.63; H, 6.43; N, 6.62. Found:C, 59.66; H, 6.28; N, 6.44.

Example 302N-[(2Z)-5-tert-butyl-3-[(cis)-(3-hydroxycyclobutyl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 302A(cis-3-(benzyloxymethyl)cyclobutoxy)(tert-butyl)dimethylsilane

To a solution of cis-3-benzyloxymethylcyclobutanol (Albany MolecularResearch Institute, 1.0 g, 5.2 mmol) in 50 mL of CH₂Cl₂ was addedimidazole (2.7 g, 39 mmol) followed by tert-butyldimethylsilyl chloride(3.9 g, 26 mmol). This mixture stirred at ambient temperature for 2hours and was quenched with 10 mL of saturated aqueous NH₄Cl. The layerswere separated and the aqueous layer was extracted with three 5 mL ofportions of CH₂Cl₂. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification via column chromatography (SiO₂, 75% hexanes in ethylacetate) afforded the title compound. MS (DCI/NH₃) m/z 307 (M+H)⁺.

Example 302B (cis-3-(tert-butyldimethylsilyloxy)cyclobutyl)methanol

A solution of Example 302A (3.7 g, 12 mmol) in 20 mL of ethanol wasdegassed and the flask was flushed with N₂. This was repeated twoadditional times. Pd/C (0.37 g, 10 wt %) was added and the mixture wasdegassed again and flushed with N₂. This was repeated two additionaltimes then the flask was put under 1 atm. of H₂ and the reaction mixturewas allowed to stir at ambient temperature for 48 hours. The mixture wasdegassed and the flask was filled with N₂ then the reaction mixture wasfiltered, concentrated under reduced pressure and purified by columnchromatography (SiO₂, 50% hexanes in ethyl acetate) to afford the titlecompound. MS (DCI/NH₃) m/z 217 (M+NH₄)⁺.

Example 302C (cis-3-(tert-butyldimethylsilyloxy)cyclobutyl)methyl4-methylbenzenesulfonate

Example 302B (1.2 g, 5.5 mmol) and p-toluenesulfonyl chloride (1.1 g,5.5 mmol) in 7 mL of CH₂Cl₂ and 7 mL of pyridine were processed as inExample 203A to afford the title compound. MS (DCI/NH₃) m/z 371 (M+H)⁺,388 (M+NH₄)⁻.

Example 302D5-tert-butyl-3-((cis-3-(tert-butyldimethylsilyloxy)cyclobutyl)methyl)thiazol-2(3H)-imine

Example 240A (0.72 g, 4.6 mmol), Example 302C (1.7 g, 4.6 mmol) andtetrabutylammonium iodide (0.85 g, 2.3 mmol) in 1.5 mL ofN,N-dimethylformamide were processed as in Example 240C to afford thetitle compound. MS (DCI/NH₃) m/z 355 (M+H)⁺.

Example 302E(Z)—N-(5-tert-butyl-3-((cis-3-(tert-butyldimethylsilyloxy)cyclobutyl)methyl)thiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

Example 302D (0.57 g, 1.6 mmol), triethylamine (0.67 mL, 4.8 mmol) andExample 205B (1.6 mmol) in 10 mL of tetrahydrofuran were processed as inExample 208D to afford the title compound. MS (DCI/NH₃) m/z 523 (M+H)⁺.

Example 302FN-[(2Z)-5-tert-butyl-3-[(cis)-(3-hydroxycyclobutyl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

To Example 302E (0.78 g, 1.5 mmol) in 10 mL of tetrahydrofuran atambient temperature was added tetrabutylammonium fluoride (1 M intetrahydrofuran, 1.8 mL, 1.8 mmol) dropwise via syringe pump over 30minutes. The reaction mixture was stirred at ambient temperature for 2hours and was concentrated under reduced pressure and purified by columnchromatography (SiO₂, 50% hexanes in ethyl acetate then 100% ethylacetate) to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm1.38 (s, 9H), 1.70-1.82 (m, 2H), 2.25-2.42 (m, 3H), 3.86 (s, 3H),4.00-4.10 (m, 1H), 4.28 (d, J=6.4 Hz, 2H), 7.07 (d, J=9.2 Hz, 1H), 7.12(s, 1H), 7.39 (dd, J=8.8, 2.7 Hz, 1H), 7.80 (d, J=2.7 Hz, 1H); MS(DCI/NH₃) m/z 409 (M+H)⁻.

Example 303N-[(2Z)-5-tert-butyl-3-[((cis)-3-hydroxy-3-methylcyclobutyl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 303A(Z)—N-(5-tert-butyl-3-((3-oxocyclobutyl)methyl)thiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

To Example 302F (0.57 g, 1.4 mmol) in 15 mL of CH₂Cl₂ was added4-methylmorpholine N-oxide (0.82 g, 7.0 mmol) followed by approximately0.5 g powdered 4 Å molecular sieves. This mixture was stirred at ambienttemperature for 15 minutes and was cooled to 0° C. andtetrapropylammonium perruthenate (49 mg, 0.14 mmol) was added inportions over 5 minutes. The mixture was stirred at 0° C. for 5 minutesand was allowed to warm to ambient temperature and stirred for anadditional 90 minutes. The mixture was filtered through Celite,concentrated under reduced pressure and purified by columnchromatography (SiO₂, 20% hexanes in ethyl acetate) to afford the titlecompound. MS (DCI/NH₃) m/z 407 (M+H)⁻.

Example 303BN-[(2Z)-5-tert-butyl-3-[((cis)-3-hydroxy-3-methylcyclobutyl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

To Example 302A (0.21 g, 0.52 mmol) in 10 mL of tetrahydrofuran at −78°C. was added a 1.6 M solution of methyllithium in diethyl ether (1.0 mL,1.6 mmol) dropwise over 5 minutes. The mixture was stirred at −78° C.for 2 hours and was slowly warmed to ambient temperature and was allowedto stir for 18 hours. The mixture was quenched with 5 mL of saturatedaqueous NH₄Cl and diluted with 5 mL of ethyl acetate. The layers wereseparated and the aqueous layer was extracted twice with 5 mL of ethylacetate. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. Purification viacolumn chromatography (SiO₂, 30% hexanes in ethyl acetate) afforded thetitle compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.32 (s, 3H), 1.38 (s,9H), 1.90-2.00 (m, 2H), 2.06-2.16 (m, 2H), 2.35-2.52 (m, 1H), 3.86 (s,3H), 4.30 (d, J=7.1 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H), 7.12 (s, 1H), 7.39(dd, J=8.8, 2.7 Hz, 1H), 7.80 (d, J=3.1 Hz, 1H); MS (DCI/NH₃) m/z 423(M+H)⁺. Anal. Calculated for C₂₁H₂₇ClN₂O₃S.0.1H₂O: C, 59.38; H, 6.45; N,6.59. Found: C, 59.17; H, 6.62; N, 6.28.

Example 3045-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-3-[((cis)-3-methoxycyclobutyl)methyl]-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 304A(Z)—N-(5-acetyl-3-(((cis)-3-methoxycyclobutyl)methyl)-4-methylthiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

Example 238A (0.57 g, 1.8 mmol), Example 301C (0.48 g, 1.8 mmol) andpotassium tert-butoxide (0.42 g, 3.5 mmol) were processed as describedin the procedure for Example 238B to afford the title compound. MS(DCI/NH₃) m/z 423 (M+H)⁺.

Example 304B5-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-3-[((cis)-3-methoxycyclobutyl)methyl]-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 304A (20 mg, 0.047 mmol) and methyllithium (1.6 M in ether, 88μL, 0.14 mmol) in 1 mL of tetrahydrofuran were processed as described inExample 239 to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm1.61 (s, 6H), 1.80-1.87 (m, 2H), 2.32-2.43 (m, 2H), 2.49 (s, 3H),3.20-3.24 (m, 1H), 3.20 (s, 3H), 3.34-3.41 (m, 1H), 3.68-3.78 (m, 1H),3.86 (s, 3H), 4.38 (d, J=6.1 Hz, 2H), 7.06 (d, J=8.8 Hz, 1H), 7.39 (dd,J=8.8, 2.7 Hz, 1H), 7.86 (d, J=2.7 Hz, 1H) MS (DCI/NH₃) m/z 439 (M+H)⁺.

Example 305N-[(2Z)-5-tert-butyl-3-[2-(2-methoxyethoxy)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 305A5-tert-butyl-3-(2-(2-methoxyethoxy)ethyl)thiazol-2(3H)-iminehydrobromide

A mixture of Example 240A (0.20 g, 1.3 mmol) and1-bromo-2-(2-methoxyethoxy)ethane (0.27 g, 1.4 mmol) was warmed to 85°C. and was allowed to stir for 24 hours. The mixture was cooled toambient temperature and the crude solids were triturated with ethanoland ether to afford the title compound. MS (DCI/NH₃) m/z 259 (M+H)⁻.

Example 305BN-[(2Z)-5-tert-butyl-3-[2-(2-methoxyethoxy)ethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 305A (0.3 g, 0.88 mmol), triethylamine (0.49 mL, 3.5 mmol) andExample 205B (0.88 mmol) in 10 mL of tetrahydrofuran and 1.5 mL ofN,N-dimethylformamide were processed as described in Example 208D toafford the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.38 (s, 9H),3.31 (s, 3H), 3.47-3.52 (m, 2H), 3.59-3.65 (m, 2H), 3.87 (dd, J=5.4 Hz,2H), 3.86 (s, 3H), 4.42 (dd, J=5.1 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H), 7.18(s, 1H), 7.39 (dd, J=8.8, 2.7 Hz, 1H), 7.82 (d, J=2.7 Hz, 1H); MS(DCI/NH₃) m/z 427 (M+H)⁺. Anal. Calculated for C₂₀H₂₇ClN₂O₄S: C, 56.26;H, 6.37; N, 6.56. Found: C, 56.06; H, 5.50; N, 6.43.

Example 306N-[(2Z)-5-tert-butyl-3-(3-methoxypropyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 306A 5-tert-butyl-3-(3-methoxypropyl)thiazol-2(3H)-imine

A mixture of Example 240A (0.20 g, 1.3 mmol) and1-bromo-3-methoxypropane (0.22 g, 1.4 mmol) was warmed to 85° C. and wasallowed to stir for 24 hours. The mixture was cooled to ambienttemperature, concentrated under reduced pressure and purified via columnchromatography (SiO₂, 10% methanol in ethyl acetate then 9:1:0.1CH₂Cl₂:methanol:NH₄OH) to afford the title compound. MS (DCI/NH₃) m/z229 (M-PH)⁺.

Example 306BN-[(2Z)-5-tert-butyl-3-(3-methoxypropyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 306A (0.25 g, 0.81 mmol), triethylamine (0.34 mL, 2.4 mmol) andExample 205B (0.81 mmol) in 10 mL of tetrahydrofuran and 1 mL ofN,N-dimethylformamide were processed as in Example 208D to afford thetitle compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.38 (s, 9H), 2.05-2.17(m, 2H), 3.32 (s, 3H), 3.41 (t, J=5.9 Hz, 2H), 3.86 (s, 3H), 4.33 (t,J=7.0 Hz, 2H), 7.07 (d, J=8.8 Hz, 1H), 7.11 (s, 1H), 7.40 (dd, J=9.0,2.9 Hz, 1H), 7.89 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 397 (M+H)⁺. Anal.Calculated for C₁₉H₂₅ClN₂O₃S: C, 57.49; H, 6.35; N, 7.06. Found: C,57.18; H, 6.21; N, 6.94.

Example 307N-[(2Z)-5-tert-butyl-3-(2-ethoxyethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 307A 5-tert-butyl-3-(2-ethoxyethyl)thiazol-2(3H)-imine

A mixture of Example 240A (0.17 g, 1.1 mmol) and 2-(bromoethyl)ether(0.20 g, 1.2 mmol) was warmed to 85° C. and was allowed to stir for 24hours. The mixture was cooled to ambient temperature, concentrated andpurified via column chromatography (SiO₂, 10% methanol in ethyl acetatethen 9:1:0.1 CH₂Cl₂:methanol:NH₄OH) to afford the title compound. MS(DCI/NH₃) m/z 229 (M+H)⁺.

Example 307BN-[(2Z)-5-tert-butyl-3-(2-ethoxyethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 307A (0.24 g, 1.05 mmol), triethylamine (0.44 mL, 3.2 mmol) andExample 205B (1.05 mmol) in 15 mL of tetrahydrofuran were processed asin Example 208D to afford the title compound. ¹H NMR (300 MHz, CD₃OD) δppm 1.14 (t, J=7.0 Hz, 3H), 1.38 (s, 9H), 3.52 (q, J=6.9 Hz, 2H), 3.81(t, J=5.3 Hz, 2H), 3.86 (s, 3H), 4.41 (t, J=5.3 Hz, 2H), 7.07 (d, J=8.8Hz, 1H), 7.14 (s, 1H), 7.39 (dd, J=8.8, 2.7 Hz, 1H), 7.83 (d, J=3.1 Hz,1H); MS (DCI/NH₃) m/z 397 (M+H)⁺. Anal. Calculated for C₁₉H₂₅ClN₂O₃S: C,57.49; H, 6.35; N, 7.06. Found: C, 57.34; H, 6.04; N, 6.94.

Example 308N-[(2Z)-5-tert-butyl-3-(3-hydroxy-3-methylbutyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 308A 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate

To a solution of 3-methylbutane-1,3-diol (2.13 mL, 20 mmol) in pyridine(20 mL) at 0° C. was added para-toluenesulfonyl chloride (3.8 g, 20mmol) in pyridine (10 mL) drop-wise over 15 minutes. This mixturestirred at ambient temperature for 3 hours and 35 mL H₂O was added andthe mixture was extracted with ethyl acetate (2×50 mL). The combinedorganics were washed with H₂O (2×50 mL), dried over MgSO₄, filtered,concentrated under reduced pressure and dried under vacuum (˜1 mm Hg) toafford the title compound. MS (ESI) m/z 276 (M+18)⁺.

Example 308BN-[(2Z)-5-tert-butyl-3-(3-hydroxy-3-methylbutyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A solution of Example 244A (75 mg, 0.23 mmol) in N,N-dimethylformamide(2 mL) was treated with NaH 60% dispersion in oil (9.5 mg, 0.23 mmol)followed by Example 308A (60 mg, 0.23 mmol). The reaction mixture wasstirred at room temperature for 18 hours, poured into water andextracted with ethyl acetate. The organic layer was washed with H₂O(2×50 mL), dried over MgSO₄, filtered, concentrated under reducedpressure and dried under vacuum (˜1 mm Hg) to afford the title compound.¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.17 (s, 6H), 1.32 (s, 9H),1.76-1.91 (m, 2H), 3.79 (s, 3H), 4.14-4.31 (m, 2H), 4.43 (s, 1H), 7.10(d, J=8.8 Hz, 1H), 7.31 (s, 1H), 7.44 (dd, J=9.0, 2.9 Hz, 1H), 7.76 (d,J=3.1 Hz, 1H); MS (ESI) m/z 411 (M+H)^(h) Anal. Calculated forC₂₀H₂₇ClN₂O₃SC, 58.45; H, 6.62; N, 6.82. Found C, 58.30; H, 6.51; N,6.71.

Example 309N-[(2Z)-5-tert-butyl-3-(3-hydroxy-3-methylbutyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 309A(Z)—N-(5-tert-butyl-4-methylthiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

A mixture of 5-tert-butyl-4-methylthiazol-2(3H)-imine (250 mg, 1.5 mmol)in tetrahydrofuran (10 mL) was treated with triethylamine (0.25 mL, 1.8mmol) and 5-chloro-2-methoxybenzoylchloride (307 mg, 1.5 mmol). Thereaction mixture was stirred at 60° C. for 18 hours then concentratedunder reduced pressure. The residue was diluted with ethyl acetate andH₂O. The organic extract was dried over MgSO₄, filtered, concentratedunder reduced pressure and dried under vacuum to afford the titlecompound (490 mg, 96% yield). MS (ESI) m/z 339 (M+H)⁺.

Example 309BN-[(2Z)-5-tert-butyl-3-(3-hydroxy-3-methylbutyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 308A and Example 309A were processed using the method describedin Example 308B to afford the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 1.19 (s, 6H), 1.38 (s, 9H), 1.65-1.81 (m,2H), 2.41 (s, 3H), 3.78 (s, 3H), 4.17-4.33 (m, 2H), 4.49 (s, 1H), 7.09(d, J=8.8 Hz, 1H), 7.43 (dd, J=8.8, 3.1 Hz, 1H), 7.78 (d, J=2.7 Hz, 1H).MS (ESI) m/z 425 (M+H)⁺. Anal. Calculated for C₂₁H₂₉ClN₂O₃S C, 59.35; H,6.88; N, 6.55. Found C, 58.83; H, 7.13; N, 6.41.

Example 310N-[(2Z)-5-tert-butyl-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Commercially available 2-bromoethyl methyl ether (Aldrich) and Example244A were processed using the method described in Example 246 to affordthe title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 1.35(s, 9H), 3.36 (s, 3H), 3.68-3.84 (m, 2H), 3.90 (s, 3H), 4.36 (t, J=5.1Hz, 2H), 6.77 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.32 (dd, J=8.8, 2.7 Hz,1H), 7.95 (d, J=2.7 Hz, 1H); MS (ESI⁻) m/z 383 (M+H)⁺; Anal. Calculatedfor C₁₈H₂₃ClN₂O₃S: C, 56.46; H, 6.05; N, 7.32. Found: C, 56.69; H, 6.02;N, 7.42.

Example 3115-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 311A(Z)—N-(5-acetyl-3-(2-methoxyethyl)-4-methylthiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

Commercially available 2-bromoethyl methyl ether (Aldrich) and Example238A were processed using the method described in Example 246 to affordthe title compound. MS (ESI⁺) m/z 383 (M+H)⁺.

Example 311B5-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-3-(2-methoxyethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 311A and commercially available methyllithium (Aldrich, 1.6 M indiethyl ether) were processed using the method described in Example 255to afford the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δppm 1.50 (s, 6H), 2.42 (s, 3H), 3.25 (s, 3H), 3.68 (t, J=5.4 Hz, 2H),3.78 (s, 3H), 4.30 (t, J=5.4 Hz, 2H), 5.62 (s, 1H), 7.09 (d, J=9.2 Hz,1H), 7.43 (dd, 1H), 7.63 (d, J=2.7 Hz, 1H); MS (ESI⁺) m/z 399 (M+H)⁺;Anal. Calculated for C₁₈H₂₃ClN₂O₄S: C, 54.20; H, 5.81; N, 7.02. Found:C, 54.30; H, 5.68; N, 6.91.

Example 312N-[(2Z)-5-tert-butyl-3-(2-methoxy-2-methylpropyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and 1-bromo-2-methoxy-2-methylpropane were processed usingthe method described in Example 246 to afford the title compound. ¹H NMR(500 MHz, CDCl₃) δ ppm 1.23 (s, 6H) 1.36 (s, 9H) 3.22 (s, 3H) 3.89 (s,3H) 4.32 (s, 2H) 6.89 (s, 1H) 6.91 (s, 1H) 7.33 (dd, J=8.9, 2.8 Hz, 1H)7.92 (d, J=2.8 Hz, 1H); MS (ESI) m/z 411 (M+H)⁺.

Example 313N-[(2Z)-3-butyl-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 313A(Z)—N-(5-acetyl-3-butyl-4-methylthiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

A mixture of Example 238A (0.40 g, 1.2 mmol), 1-bromobutane (0.16 mL,1.5 mmol), and potassium t-butoxide (0.22 g, 1.9 mmol) in 5 mLN,N-dimethylformamide was warmed to 65° C. and stirred for 20 hours. Themixture was cooled to ambient temperature quenched with 5 mL ofsaturated aquesous NH₄Cl and diluted with 5 mL of ethyl acetate. Thelayers were separated and the aqueous phase was extracted twice with 5mL of ethyl acetate. The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification via column chromatography (SiO₂, 40% hexanes in ethylacetate) afforded the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.04(t, J=7.3 Hz, 3H), 1.42-1.55 (m, 2H), 1.77-1.90 (m, 2H), 2.51 (s, 3H),2.76 (s, 3H), 3.88 (s, 3H), 4.32-4.41 (m, 2H), 7.10 (d, J=8.8 Hz, 1H),7.45 (dd, J=8.8, 2.7 Hz, 1H), 7.99 (d, J=3.1 Hz, 1H); MS (DCI/NH₃) m/z381 (M+H)⁺. Anal. Calculated for C₁₈H₂₁ClN₂O₃S: C, 56.76; H, 5.56; N,7.35. Found: C, 56.68; H, 5.49; N, 7.26.

Example 313BN-[(2Z)-3-butyl-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

To the product of Example 313A (90 mg, 0.24 mmol) in 5 mL of THF at −78°C. was added a solution of methyllithium (1.6 M in diethyl ether, 0.44mL, 0.71 mmol) dropwise over 5 minutes. The mixture was stirred at −78°C. for 4 hours and was slowly warmed to ambient temperature and allowedto stir for 12 hours. The mixture was quenched with 3 mL of saturatedaqueous NH₄Cl and diluted with 5 mL of ethyl acetate. The layers wereseparated and the aqueous phase was extracted twice with 5 mL ethylacetate. The combined organic extracts were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. Purification viacolumn chromatography (SiO₂, 20% hexanes in ethyl acetate) afforded thetitle compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.02 (t, J=7.3 Hz, 3H),1.39-1.54 (m, 2H), 1.61 (s, 6H), 1.71-1.84 (m, 2H), 2.51 (s, 3H), 3.85(s, 3H), 4.23-4.31 (m, 2H), 7.06 (d, J=8.8 Hz, 1H), 7.39 (dd, J=9.0, 2.9Hz, 1H), 7.87 (d, J=3.1 Hz, 1H); MS (DCI/NH₃) m/z 397 (M+H)⁺. Anal.Calculated for C₁₉H₂₅ClN₂O₃S: C, 57.49; H, 6.35; N, 7.06. Found: C,57.36; H, 6.33; N, 6.85.

Example 314(5-chloro-N-[(2Z)-3-(cyclobutylmethyl)-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 314A(Z)—N-(5-acetyl-3-(cyclobutylmethyl)-4-methylthiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

A mixture of the product of Example 238A (0.75 g, 2.3 mmol),(bromomethyl)cyclobutane (0.31 mL, 2.8 mmol), and potassium t-butoxide(0.41 g, 3.5 mmol) in 7 mL N,N-dimethylformamide was warmed to 65° C.and stirred for 16 hours. The mixture was cooled to ambient temperature,quenched with 5 mL of saturated aqueous NH₄Cl and diluted with 10 mL ofethyl acetate. The layers were separated and the aqueous phase wasextracted twice with 7 mL of ethyl acetate. The combined organicextracts were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. Purification via column chromatography (SiO₂,40% hexanes in ethyl acetate) afforded the title compound. ¹H NMR (300MHz, CD₃OD) δ ppm 1.88-2.15 (m, 6H), 2.51 (s, 3H), 2.75 (s, 3H),2.83-2.96 (m, 1H), 3.89 (s, 3H), 4.46 (d, J=7.5 Hz, 2H), 7.11 (d, J=9.2Hz, 1H), 7.45 (dd, J=8.8, 2.7 Hz, 1H), 7.99 (d, J=3.1 Hz, 1H); MS(DCI/NH₃) m/z 393 (M+H)⁺. Anal. Calculated for C₁₉H₂₁ClN₂O₃S: C, 58.08;H, 5.39; N, 7.13. Found: C, 58.06; H, 5.20; N, 7.06.

Example 314B(5-chloro-N-[(2Z)-3-(cyclobutylmethyl)-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

To the product of Example 314A (0.13 g, 0.33 mmol) in 5 mL oftetrahydrofuran at −78° C. was added a solution of methyllithium (1.6 Min diethyl ether, 0.62 mL, 0.99 mmol) dropwise over 5 minutes. Themixture was stirred at −78° C. for 1 hour then slowly warmed to ambienttemperature and allowed to stir for 16 hours. The mixture was quenchedwith 5 mL of saturated aqueous NH₄Cl and diluted with 5 mL of ethylacetate. The layers were separated and the aqueous phase was extractedtwice with 5 mL ethyl acetate. The combined organic extracts were driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.Purification via column chromatography (SiO₂, 30% hexanes in ethylacetate) afforded the title compound. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.61(s, 6H), 1.86-2.13 (m, 6H), 2.49 (s, 3H), 2.79-2.93 (m, 1H), 3.86 (s,3H), 4.37 (d, J=7.1 Hz, 2H), 7.06 (d, J=8.8 Hz, 1H), 7.39 (dd, J=8.8,2.7 Hz, 1H), 7.87 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 409 (M+H)⁺. Anal.Calculated for C₂₀H₂₅ClN₂O₃S: C, 58.74; H, 6.16; N, 6.85. Found: C,58.70; H, 6.12; N, 6.74.

Example 315N-[(2Z)-5-tert-butyl-3-[(2S)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 315A5-tert-Butyl-3-[(S)-1-(tetrahydro-furan-2-yl)methyl]-3H-thiazol-2-ylideneamine

To a solution of 3,3-dimethylbutanal (Aldrich) (1.52 mL, 12.1 mmol) and(S)-(tetrahydrofuran-2-yl)methanamine (Aldrich) (1.00 g, 9.89 mmol) in12 mL of acetonitrile was added 1.20 g of molecular sieves (4 Å beads,8-12 mesh). The mixture was stirred for 12 h at 22° C. The mixture wasfiltered and to the filtrate was added potassium thiocyanate (1.42 g,14.6 mmol). The temperature was adjusted at 50° C. and the mixture wasstirred until all solids were dissolved, then iodine (5.58 g, 22.0 mmol)was added. The reaction was stirred at 50° C. for 12 h. The reaction wascooled to room temperature and diluted with EtOAc. The solution waswashed with a solution of sodium bisulfate. The aqueous layers wasbrought to pH=9 by adding aq. NaOH (25%) and extracted with EtOAc. Theorganic extracts were combined, dried with sodium sulfate, filtered, andconcentrated. The residue was crystallized from EtOAc/Hexane to give thetitle compound. MS (ESI⁻) m/z 241 (M+H)⁺.

Example 315BN-[(2Z)-5-tert-butyl-3-[(2S)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The products from Example 315A and 5-chloro-2-methoxy-benzoic acid wereprocessed using the method described in Example 300 to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.35 (s, 9H), 1.62-1.95 (m, 3H),2.00-2.12 (m, 1H), 3.72-3.87 (m, 2H), 3.90 (s, 3H), 4.18-4.34 (m, 2H),4.42 (dd, J=12.0, 2.4 Hz, 1H), 6.86 (s, 1H), 6.90 (d, J=8.8 Hz, 1H),7.32 (dd, J=8.8, 2.7 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H). MS (ESI⁺) m/z 409(M+H)⁺.

Example 3165-chloro-2-methoxy-N-[(2Z)-4,4,6,6-tetramethyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]benzamideExample 316A4,4,6,6-Tetramethyl-3-[(R)-1-(tetrahydro-furan-2-yl)methyl]-4,6-dihydro-3H-furo[3,4-a]thiazol-2-ylideneamine

2,2,5,5-tetramethyldihydrofuran-3(2H)-one (Aldrich) and(R)-(tetrahydrofuran-2-yl)methanamine (Aldrich) were processed using themethod described in Example 315A to afford the title compound. MS (ESI⁺)m/z 283 (M+H)⁺.

Example 316B5-chloro-2-methoxy-N-[(2Z)-4,4,6,6-tetramethyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]benzamide

The product from Example 316A and 5-chloro-2-methoxy-benzoic acid wereprocessed using the method described in Example 300 to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.52 (s, 3H), 1.55 (s, 3H), 1.58(s, 3H), 1.66 (s, 3H), 1.70-1.82 (m, 1H), 1.90-2.02 (m, 2H), 2.10-2.24(m, 1H), 3.70-3.82 (m, 2H), 3.83-3.89 (m, 1H), 3.90 (s, 3H), 4.42 (dd,J=13.6, 3.7 Hz, 1H), 4.54-4.66 (m, 1H), 6.91 (d, J=8.8 Hz, 1H), 7.35(dd, J=8.8, 2.7 Hz, 1H), 7.99 (d, J=2.7 Hz, 1H). MS (ESI⁺) m/z 451(M+H)⁺.

Example 317N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-cyano-2-methoxybenzamideExample 317A5-tert-butyl-3-[(R)-1-(tetrahydro-furan-2-yl)methyl]-3H-thiazol-2-ylideneamine

3,3-dimethylbutanal (Aldrich) and (R)-(tetrahydrofuran-2-yl)methanamine(Aldrich) were processed using the method described in Example 315A toafford the title compound. MS (ESI⁺) m/z 241 (M+H)⁺.

Example 317B 5-cyano-2-methoxy-benzoic acid methyl ester

A mixture of 3-bromo-4-methoxybenzonitrile (Aldrich) (10.0 g, 47.2mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (Aldrich) (1.00 g, 1.22 mmol) andtriethylamine (12.5 mL, 89.7 mmol) in 100 mL of methanol in a highpressure vessel was heated to 100° C. at 60 psi of CO₂ for 4 h. Themixture was cooled to room temperature and filtered. The mixture wasconcentrated under reduced pressure to afford the title compound. ¹H NMR(500 MHz, CDCl₃) δ ppm 3.91 (s, 3H), 3.98 (s, 3H), 7.06 (d, J=8.5 Hz,1H), 7.76 (dd, J=8.7, 2.3 Hz, 1H), 8.10 (d, J=2.1 Hz, 1H).

Example 317C 5-cyano-2-methoxy-benzoic

A mixture of Example 317B (6.10 g, 31.9 mmol) and lithium hydroxidemonohydrate (5.36 g, 128 mmol) in 150 mL of THF/water (2/1) was stirredat 22° C. for 3 h. The organic solvent was evaporated under reducedpressure and the aqueous solution was acidified to pH 2 with 6 N HCl.The mixture was extracted with dichloromethane. The organic extractswere dried over sodium sulfate, filtered, and concentrated under reducedpressure to afford the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm4.15 (s, 3H), 7.17 (d, J=8.8 Hz, 1H), 7.86 (dd, J=8.7, 2.3 Hz, 1H), 8.47(d, J=2.1 Hz, 1H), 9.50-10.21 (brs, 1H).

Example 317DN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-cyano-2-methoxybenzamide

The products from Example 317A and Example 317C were processed using themethod described in Example 300 to afford the title compound. ¹H NMR(300 MHz, CDCl₃) δ ppm 1.36 (s, 9H), 1.60-1.97 (m, 3H), 2.01-2.16 (m,1H), 3.73-3.89 (m, 2H), 3.97 (s, 3H), 4.18-4.34 (m, 2H), 4.39 (dd,J=12.0, 2.4 Hz, 1H), 6.90 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.67 (dd,J=8.8, 2.4 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H). MS (ESI⁺) m/z 400 (M+H)⁺.

Example 318N-[(2Z)-4-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 318A4-tert-butyl-3-[(R)-1-(tetrahydro-furan-2-yl)methyl]-3H-thiazol-2-ylideneamine

3,3-dimethylbutan-2-one (Aldrich) and(R)-(tetrahydrofuran-2-yl)methanamine (Aldrich) were processed using themethod described in Example 315A to afford the title compound. MS (ESI⁺)m/z 241 (M+H)⁺.

Example 318BN-[(2Z)-4-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

The product from Example 318A and 5-chloro-2-methoxy-benzoic acid wereprocessed using the method described in Example 300 to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) −2.23 (m, 1H), 3.67-3.76 (m, 1H),3.83-3.89 (m, 1H), 3.90 (s, 3H), 4.40 (dd, J=15.0, 7.5 Hz, 1H),4.57-4.68 (m, 2H), 6.35 (s, 1H), 6.91 (d, J=8.7 Hz, 1H), 7.33 (dd,J=8.7, 2.8 Hz, 1H), 8.04 (d, J=2.8 Hz, 1H). MS (ESI⁺) m/z 409 (M+H)⁺.

Example 319N-[(2Z)-5-tert-butyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 319 AN-(5-tert-butyl-4-methylthiazol-2-yl)-5-chloro-2-methoxybenzamide

To 5-tert-butyl-4-methylthiazol-2-amine (Matrix, 204 mg, 1.2 mmol) inCH₂Cl₂ (10 ml) at 0° C. was added Example 205B (246 mg, 1.2 mmol),followed by triethylamine (0.2 ml, 1.44 mmol). The mixture was stirredat room temperature for 4 hours and checked with LC/MS. When thestarting material disappeared, water (20 ml) and CH₂Cl₂ (20 ml) wereadded. The organic layer was washed with brine and concentrated underreduced pressure. The residue was purified by chromatography on a silicagel cartridge, eluting with ethyl acetate/hexane in 5-30% gradient toyield the title compound (305 mg, 75%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm11.64 (s, 1H), 7.47-7.77 (m, 2H), 7.22 (d, J=8.82 Hz, 1H), 3.89 (s, 3H),2.34 (s, 3H), 1.39 (s, 9H). MS (ESI) m/z 339 [M+H]⁺, 337 {M−H]⁻.

Example 319BN-[(2Z)-5-tert-butyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

To the mixture of Example 319A (160 mg, 0.472 mmol), Example 208A (182mg, 0.71 mmol) and K₂CO₃ (131 mg, 0.944 mmol) in toluene (6 ml) wereadded phase transfer agents of n-Bu₄NI (5%) and n-Bu₄NHSO₄ (5%). Thereaction mixture was heated at 100° C. for 24 hrs, and then cooled toambient temperature and filtered. The solid was washed with ethylacetate (10 mL×2) and the filtrate was concentrated under reducedpressure. The residue was purified by preparative reverse phase HPLCusing a gradient of 10% to 100% acetonitrile: ammonium acetate (10 mM)to afford the title compound (101 mg, 50.6%). ¹H NMR (300 MHz, DMSO-d6)δ ppm 7.64 (d, J=2.71 Hz, 1H), 7.40-7.46 (m, 1H), 7.09 (d, J=8.81 Hz,1H), 4.23-4.38 (m, 2H), 4.03-4.13 (m, 1H), 3.74-3.83 (m, 4H), 3.59-3.68(m, 1H), 2.41 (s, 3H), 1.63-2.02 (m, 4H), 1.38 (s, 9H); MS (ESI) m/z 423[M+H]⁺.

Example 3205-chloro-2-methoxy-N-{(2Z)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4,5,6,7,8-hexahydro-2H-4,7-epoxycyclohepta[d][1,3]thiazol-2-ylidene}benzamideExample 320A3-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4,5,6,7,8-hexahydro-2H-4,7-epoxycyclohepta[d][1,3]thiazol-2-imine

A mixture of 8-oxabicyclo[3.2.1]octan-2-one (obtained as described inVogel et al. Tetrahedron 1993, 49 (8), 1649-1664) (0.53 g, 4.2 mmol),(R)-(tetrahydrofuran-2-yl)methanamine (0.43 mL, 4.2 mmol) and 1 g of 4 Åmolecular sieves (8-12 mesh beads) in acetonitrile (4 mL) was stirred atambient temperature for 16 h. The material was filtered through Celite®with acetonitrile (additional 10 mL) then the filtrate treated withpotassium thiocyanate (0.54 g, 5.6 mmol) was added and the mixture waswarmed to 50° C. Iodine (2.1 g, 8.4 mmol) was added and the mixturestirred at 50° C. for 72 h. The mixture was cooled to ambienttemperature and was concentrated under reduced pressure. The crudematerial was diluted with 20 mL CH₂Cl₂ and was stirred with sodiummetabisulfite (20 mL of 20% aqueous solution) for 15 min. The layerswere separated and the aqueous layer was extracted 3×10 mL CH₂Cl₂. Thecombined organics were dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give the crude material (1.0 g, 3.8 mmol, 89%yield) which was carried on without further purification. MS (DCI/NH₃)m/z 267 (M+H)⁺.

Example 320B5-chloro-2-methoxy-N-{(2Z)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4,5,6,7,8-hexahydro-2H-4,7-epoxycyclohepta[d][1,3]thiazol-2-ylidene}benzamide

To a solution of the product of Example 320A (1.0 g, 3.8 mmol) in THF(25 mL) was added triethylamine (1.6 mL, 11.3 mmol). To this mixture wasadded Example 205B (0.77 g, 3.8 mmol). The mixture was warmed to 50° C.and allowed to stir for 16 hours. The mixture was cooled to ambienttemperature then was quenched with saturated, aqueous NaHCO₃, extractedwith EtOAc, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The mixture was purified by column chromatography (SiO₂, 40%hexanes in EtOAc) and then was further purified by HPLC (Waters XTerraRP18 5μ column, 30×100 mm, 40 mL/min flow rate, 5-95% gradient ofacetonitrile in 0.1% aqueous trifluoroacetic acid over 22 min, UVdetection at 254 nm) to give the title compound (0.40 g, 0.92 mmol, 25%yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.64-2.02 (m, 4H), 2.08-2.33 (m,5H), 3.19 (dt, J=10.9, 5.4 Hz, 1H), 3.69-3.88 (m, 2H), 3.88-3.95 (m,1H), 3.90 (s, 3H), 4.17-4.78 (m, 2H), 4.80-4.89 (m, 1H), 5.29 (dd,J=12.2, 5.8 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 7.36 (ddd, J=8.8, 2.7, 1.4Hz, 1H), 7.96 (d, J=2.7 Hz, 1H); MS (DCI/NH₃) m/z 435 (M+H)⁺; Anal.calculated for C₂₁C₂₃ClN₂O₄S.0.5 CF₃CO₂H: C, 53.71; H, 4.81; N, 5.69.Found: C, 53.95; H, 4.95; N, 5.80.

Example 3215-chloro-2-methoxy-N-[(2Z)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazol-2(3H)-ylidene]benzamideExample 321A(R)-3-((tetrahydrofuran-2-yl)methyl)-3,4,6,7-tetrahydro-2H-pyrano[3,4-d]thiazol-2-imine

Commercially available dihydro-2H-pyran-3(4H)-one (Small Molecules Inc),(R)-(tetrahydrofuran-2-yl)methanamine (Aldrich), potassium thiocyanate(Aldrich) and iodine (Aldrich) were processed using the method describedin Example 315A to afford the title compound. LCMS (ESI⁺) m/z 241(M+H)⁺.

Example 321B5-chloro-2-methoxy-N-[(2Z)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazol-2(3H)-ylidene]benzamide

Example 321A and 5-chloro-2-methoxybenzoic acid (Aldrich) were processedusing the method described in Example 58 to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.49-1.74 (m, 1H), 1.75-1.89 (m, 2H),1.91-2.06 (m, 1H), 2.67 (t, J=5.4 Hz, 2H), 3.57-3.68 (m, 1H), 3.72-3.83(m, 1H), 3.79 (s, 3H), 3.87-3.95 (m, 3H), 4.16-4.35 (m, 2H), 4.59-4.78(m, 2H), 7.12 (d, J=8.8 Hz, 1H), 7.46 (dd, J=8.8, 2.7 Hz, 1H), 7.69 (d,J=2.7 Hz, 1H); MS (ESI⁺) m/z 409 (M+H); Anal. Calculated forC₁₉H₂₁ClN₂O₄S: C, 55.81; H, 5.18; N, 6.85. Found: C, 55.88; H, 5.00; N,6.84.

Example 3225-chloro-2-methoxy-N-{(2Z)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene}benzamideExample 322A 6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-amine

Commercially available dihydro-2H-pyran-4(3H)-one (Aldrich), pyrrolidine(Aldrich), p-toluenesulfonic acid monohydrate (Aldrich) sulfur (Aldrich)and cyanamide (Aldrich) were processed using the method described inExample 240A to afford the title compound. MS (ESI⁺) m/z 157 (M+H)⁺.

Example 322B(Z)-5-chloro-N-(6,7-dihydro-1H-pyrano[4,3-d]thiazol-2(4H)-ylidene)-2-methoxybenzamide

Example 322A and 5-chloro-2-methoxybenzoic acid (Aldrich) were processedusing the method described in Example 58 to afford the title compound.MS (ESI⁺) m/z 325 (M+H)⁺.

Example 322C5-chloro-2-methoxy-N-{(2Z)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene}benzamide

Example 322B and Example 208A were processed using the method describedin Example 246 to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.60-2.05 (m, 4H), 2.64-2.88 (m, 2H), 3.56-3.69 (m, 1H), 3.73-3.84(m, 1H), 3.79 (s, 3H), 3.95 (t, J=5.6 Hz, 2H), 3.97-4.12 (m, 1H),4.19-4.34 (m, 2H), 4.58 (s, 2H), 7.12 (d, J=9.2 Hz, 1H), 7.46 (dd,J=8.8, 2.7 Hz, 1H), 7.69 (d, J=2.7 Hz, 1H); MS (ESI⁺) m/z 409 (M+H)⁻;Anal. Calculated for C₁₉H₂₁ClN₂O₄S: C, 55.81; H, 5.18; N, 6.85. Found:C, 55.77; H, 4.93; N, 6.72.

Example 323N-[(2Z)-5-tert-butyl-3-(2-morpholin-4-ylethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 323A 5-tert-butyl-3-(2-morpholinoethyl)thiazol-2(3H)-imine

Commercially available 3,3-dimethylbutanal (Aldrich),2-morpholinoethanamine (Aldrich), potassium thiocyanate (Aldrich) andiodine (EMD chemicals) were processed using the method described inExample 315A to afford the title compound. MS (ESI⁺) m/z 270 (M+H)⁺.

Example 323BN-[(2Z)-5-tert-butyl-3-(2-morpholin-4-ylethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 323A and Example 205B were processed using the method describedin Example 244A to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 1.32 (s, 9H), 2.39-2.49 (m, 4H), 2.69 (t, J=6.3 Hz, 2H), 3.46-3.58(m, 4H), 3.78 (s, 3H), 4.25 (t, J=6.5 Hz, 2H), 7.10 (d, J=8.7 Hz, 1H),7.30 (s, 1H), 7.44 (dd, J=8.7, 2.8 Hz, 1H), 7.66 (d, J=2.8 Hz, 1H); MS(ESI⁺) m/z 438 (M+H)⁺.

Example 324N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-hydroxybenzamide

Example 317A and 5-chloro-2-hydroxybenzoic acid (Aldrich) were processedusing the method described in Example 58 to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.34 (s, 9H), 1.59-1.75 (m, 1H),1.77-1.94 (m, 2H), 1.94-2.08 (m, 1H), 3.58-3.72 (m, 1H), 3.75-3.88 (m,1H), 4.23-4.34 (m, 3H), 6.94 (d, J=8.8 Hz, 1H), 7.37-7.48 (m, 1H), 7.45(s, 1H), 7.95 (d, J=2.7 Hz, 1H), 13.02 (s, 1H); MS (ESI⁺) m/z 395(M+H)⁺.

Example 325N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide

Example 317A and 2-methoxy-5-(trifluoromethyl)benzoyl chloride (JRDFluorochemicals Ltd) were processed using the method described inExample 244A to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.32 (s, 9H), 1.58-1.73 (m, 1H), 1.74-1.86 (m, 2H), 1.85-1.96 (m,1H), 3.57-3.71 (m, 1H), 3.73-3.83 (m, 1H), 3.87 (s, 3H), 4.19 (dd,J=5.9, 1.6 Hz, 2H), 4.31 (dd, 1H), 7.29 (s, 1H), 7.27 (s, 1H), 7.77 (dd,J=9.1, 2.4 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H); MS (ESI⁺) m/z 443 (M+H)⁺.

Example 326N-[(2Z)-5-tert-butyl-3-tetrahydro-2H-pyran-4-yl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 326A5-tert-butyl-3-(tetrahydro-2H-pyran-4-yl)thiazol-2(3H)-imine

Commercially available 3,3-dimethylbutanal (Aldrich),tetrahydro-2H-pyran-4-amine (Matrix), potassium thiocyanate (Aldrich)and iodine (EMD chemicals) were processed using the method described inExample 315A to afford the title compound. MS (ESI⁺) m/z 241 (M+H)⁺.

Example 326BN-[(2Z)-5-tert-butyl-3-tetrahydro-2H-pyran-4-yl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 326A and Example 205B were processed using the method describedin Example 244A to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 1.32 (s, 9H), 1.86 (dd, J=12.0, 2.5 Hz, 2H), 2.03-2.22 (m, 2H),3.46 (t, J=11.7 Hz, 2H), 3.79 (s, 3H), 3.93-4.03 (m, 2H), 4.81-5.16 (m,1H), 7.11 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.44 (dd, J=8.8, 2.7 Hz, 1H),7.62 (d, J=3.1 Hz, 1H); MS (ESI m/z 409 (M+H); Anal. Calculated forC₂₀C₂₅ClN₂O₃S: C, 58.74; H, 6.16; N, 6.85. Found: C, 58.59; H, 6.24; N,6.76.

Example 327N-[(2Z)-5-tert-butyl-3-{2-[(cis)-2,6-dimethylmorpholin-4-yl]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 327A5-tert-butyl-3-(2-((cis)-2,6-dimethylmorpholino)ethyl)thiazol-2(3H)-imine

Commercially available 3,3-dimethylbutanal (Aldrich),4-(2-aminoethyl)-cis-2,6-dimethylmorpholine (Oakwood), potassiumthiocyanate (Aldrich) and iodine (EMD chemicals) were processed usingthe method described in Example 315A to afford the title compound. MS(ESI⁺) m/z 298 (M+H)⁺.

Example 327BN-[(2Z)-5-tert-butyl-3-{2-[(cis)-2,6-dimethylmorpholin-4-yl]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 327A and 5-chloro-2-methoxybenzoic acid (Aldrich) were processedusing the method described in Example 58 to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.97 (s, 3H), 0.99 (s, 3H), 1.31 (s,9H), 1.68 (t, J=10.5 Hz, 2H), 2.66 (t, J=6.4 Hz, 2H), 2.80 (d, J=10.2Hz, 2H), 3.35-3.50 (m, 2H), 3.78 (s, 3H), 4.25 (t, J=6.3 Hz, 2H), 7.10(d, J=8.8 Hz, 1H), 7.30 (s, 1H), 7.44 (dd, J=8.8, 2.7 Hz, 1H), 7.67 (d,J=2.7 Hz, 1H); MS (ESI⁺) m/z 466 (M+H)⁺; Anal. Calculated forC₂₃H₃₂ClN₃O₃S.0.5H₂O.0.1C₄H₈O₂: C, 58.09; H, 7.04; N, 8.68. Found: C,57.84; H, 6.96; N, 8.58.

Example 328N-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 328A (R)-5-(tosylmethyl)dihydrofuran-2(3H)-one

(R)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (1.0 g, 8.6 mmol) wasprocessed using the method described in Example 162A to afford the titlecompound. MS (ESI) m/z 288 (M+18)⁺.

Example 328BN-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and Example 328A were processed using the method describedin Example 238B to afford the title compound. 1H NMR (500 MHz, CDCl₃) δppm 1.35 (s, 9H) 2.08-2.19 (m, 1H) 2.34-2.48 (m, 2H) 2.49-2.61 (m, 1H)3.90 (s, 3H) 4.39 (dd, J=14.34, 6.10 Hz, 1H) 4.55 (dd, J=14.65, 3.05 Hz,1H) 4.92-4.99 (m, 1H) 6.75 (s, 1H) 6.91 (d, J=8.85 Hz, 1H) 7.34 (dd,J=8.85, 2.75 Hz, 1H) 7.92 (d, J=2.75 Hz, 1H); MS (ESI) m/z 423 (M+H)⁺.

Example 3295-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(2,2,2-trifluoroethoxy)benzamide

Example 280 B was processed using the method described in Example 255 toafford the title compound. 1H NMR (500 MHz, CDCl₃) δ ppm 1.63-1.74 (m,1H) 1.66 (d, J=10.68 Hz, 6H) 1.88-1.98 (m, 3H) 2.08-2.16 (m, 1H) 2.56(s, 3H) 3.74 (dd, J=14.04, 7.32 Hz, 1H) 3.88 (dd, J=15.26, 7.02 Hz, 1H)3.97 (dd, J=14.04, 7.93 Hz, 1H) 4.33-4.40 (m, 1H) 4.46 (dd, J=17.09,8.54 Hz, 2H) 4.55 (dd, J=13.73, 3.05 Hz, 1H) 7.02 (d, J=8.85 Hz, 1H)7.33 (dd, J=8.85, 2.75 Hz, 1H) 7.99 (d, J=2.75 Hz, 1H); MS (ESI) m/z 493(M+H)⁺.

Example 330N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-[(E)-(hydroxyimino)methyl]benzamide

A mixture of Example 331B (0.020 g, 0.054 mmmol) and hydroxylaminehydrochloride (0.004 g, 0.054 mmol) in pyridine (5 mL) was stirred atroom temperature for 8 h. The mixture was concentrated under reducedpressure and the residue was partitioned between EtOAc and water. Theorganic layer was washed with water, brine, dried with MgSO₄, filtered,and concentrated under reduced pressure to afford 17 mg of product. ¹HNMR (300 MHz-DMSO-d₆) δ 1.33 (s, 9H), 1.62 (m, 1H), 1.84 (m, 2H), 1.99(m, 1H), 3.65 (m, 1H), 3.80 (m, 1H), 4.26 (m, 3H), 7.36 (s, 1H), 7.55(dd, J=9 Hz, 3 Hz, 1H), 7.78 (d, J=9 Hz, 1H), 8.04 (d, J=3 Hz, 1H), 8.87(s, 1H), 11.27 (s, 1H); MS (DCI/NH₃) m/z 422 (M+H)⁺.

Example 331N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-formylbenzamideExample 331A methylN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-N′-cyanoimidothiocarbamate

A mixture of Example 240C (0.361 g, 1.5 mmol) and dimethylcyanocarbonimidodithioate (0.219 g, 1.5 mmol) in THF (35 mL) was treatedwith triethylamine (0.21 mL, 1.5 mmol) and the resulting mixture wasstirred at 45° C. for 12 h. The mixture was concentrated under reducedpressure and the residue was purified by chromatography (hexane-EtOAc1:1) to afford 430 mg of the title compound. ¹H NMR (300 MHz-DMSO-d₆) δ1.31 (s, 9H), 1.60 (m, 1H), 1.82 (quintet, J=7 Hz, 2H), 1.95 (m, 1H),2.53 (s, 3H), 3.65 (m, 1H), 3.75 (m, 1H), 4.26 (m, 3H), 7.43 (s, 1H); MS(DCI/NH₃) m/z 339 (M+H)⁺.

Example 331BN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-formylbenzamide

To a mixture of Example 331A (0.102 g, 0.3 mmol),5-chloro-2-formylboronic acid (0.184 g, 1 mmol), copper(1)acetate (0.123g, 1 mmol) in DME (25 mL) were addedtris(dibenzylideneacetone)dipalladium(0) 0.045 g, 0.05 mmol) andtriethyl phosphate (0.024 mg, 0.14 mmol) and the mixture was refluxedfor 16 h. The mixture was then concentrated under reduced pressure andthe residue was chromatographed (SiO₂; hexane-EtOAc 1:1) to afford 30 mgof the title compound. ¹H NMR (300 MHz-DMSO-d₆) δ 1.33 (s, 9H), 1.62 (m,1H), 1.84 (m, 2H), 1.99 (m, 1H), 3.65 (m, 1H), 3.80 (m, 1H), 4.26 (m,3H), 7.36 (s, 1H), 7.70 (m, 2H), 8.06 (d, J=3 Hz, 1H), 10.53 (s, 1H); MS(DCI/NH₃) m/z 407 (M+H)⁺.

Example 332N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-N′-(1,1-dimethylpropyl)ureaExample 332A (R,Z)-4-nitrophenyl5-tert-butyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidenecarbamate

In a 20 mL vial, Example 317A was dissolved in dichloromethane (5 ml).Triethylamine (0.417 g, 4.12 mmol) was added followed by addition of4-nitrophenylcarbonyl chloridate (0.755 g, 3.74 mmol) and the reactionwas stirred for 2 hrs. The reaction was washed with water, dried withsodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by silica gel flash chromatography using 0-30% ethyl acetate inhexanes provided the title compound as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.29 (s, 9H) 1.73-1.87 (m, 3H) 1.87-1.96 (m, 1H) 3.65 (m,1H) 3.75 (m, 1H) 4.03 (m, 2H) 4.19 (m, 1H) 7.22 (s, 1H) 7.41-7.49 (m,2H) 8.24-8.30 (m, 2H). MS (DCI) m/z 406 (M+H)⁺.

Example 332BN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-N′-(1,1-dimethylpropyl)urea

To a 10 mL microwave vial, Example 332A (100 mg, 0.247 mmol) wasdissolved in acetonitrile (1.5 ml) followed by addition of2-methylbutan-2-amine (32.2 mg, 0.370 mmol) and heated in a microwavereactor at 140° C. for 10 min. The reaction was concentrated and theresidue was purified by reverse phase HPLC using a Waters Sunfire C8column (30×5 mm) eluting with a gradient of acetonitrile and 0.1%trifluoroacetic acid in water at a flow rate of 50 mL/min. Fractionsselected by mass spectrometry to provide the title compound as a TFAsalt. ¹H NMR (300 MHz, DMSO-D6) δ ppm 0.79 (t, J=7.34 Hz, 3H) 1.23 (s,6H) 1.27 (s, 9H) 1.54 (m, 1H) 1.67 (m, 2H) 1.77-1.88 (m, 2H) 1.95 (m,1H) 3.61-3.69 (m, 1H) 3.75-3.83 (m, 1H) 3.98-4.11 (m, 2H) 4.19 (m, 1H)6.65 (s, 1H) 7.11 (s, 1H). MS (DCI) m/z 354 (M+H)⁺.

Example 333N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-N′-(1-methyl-1-phenylethyl)urea

The title compound was prepared and purified as described in Example332B, substituting cumylamine for 2-methylbutan-2-amine. ¹H NMR (300MHz, CDCl₃) δ ppm 1.20-1.30 (m, 9H) 1.55 (s, 6H) 1.65 (s, 2H) 1.79-1.90(m, 2H) 3.72-3.86 (m, 2H) 3.93 (dd, J=14.48, 6.54 Hz, 1H) 4.11 (s, 1H)4.19 (s, 1H) 5.53 (s, 1H) 6.56 (s, 1H) 7.12-7.22 (m, 1H) 7.27-7.35 (m,2H) 7.46 (d, J=7.54 Hz, 2H). MS (DCI) m/z 402 (M+H)⁺. Anal. Calculatedfor C₁₆H₁₆BrClN₂O₂S: C, 65.41; H, 7.74; N, 10.23. Found: C, 65.8; H,7.78; N, 10.46.

Example 334N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-N′-(2-hydroxy-1,1-dimethylethyl)urea

The title compound was prepared and purified as described in Example332B, substituting 2-amino-2-methyl-1-propanol for 2-methylbutan-2-amine¹H NMR (300 MHz, CD₃OD) δ ppm 1.34 (s, 6H) 1.38 (s, 9H) 1.64 (m, 1H)1.88-1.98 (m, 2H) 2.12 (m, 1H) 3.58 (s, 2H) 3.76 (m, 1H) 3.90 (m, 1H)4.13 (m, 1H) 4.26 (m, 2H) 7.26 (s, 1H). MS (DCI) m/z 356 (M+H)⁺.

Example 335 methylN-({[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-2-methylalaninate

In a 20 mL microwave vial, Example 332A (60 mg, 0.148 mmol) wasdissolved in acetonitrile (1.5 ml), followed by addition oftriethylamine (0.045 ml, 0.326 mmol) and 2-amino isobutyric acid methylester hydrochloride (45.5 mg, 0.296 mmol). The reaction mixture wasmicrowaved at 120° C. for 20 min. The reaction was concentrated and theresidue was purified according to Example 332B. ¹H NMR (300 MHz, CD₃OD)δ ppm 1.34 (s, 9H) 1.52 (s, 6H) 1.63 (m, 1H) 1.91 (m, 2H) 2.09 (m, 1H)3.63-3.74 (s, 3H) 3.77 (m, 1H) 3.90 (m, 1H) 4.07 (m, 1H) 4.23 (m, 2H),7.08 (s, 1H). MS (DCI) m/z 384 (M+H)⁺. Anal. Calculated for C₁₈H₂₉N₃O₄S0.75 TFA: C, 49.94; H, 6.39; N, 8.96. Found: C, 50.28; H, 6.02; N, 9.05.

Example 336N-[(2Z)-5-tert-butyl-3-(1,3-oxazol-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A (0.125 g, 0.386 mmol) in DMF (2 mL) was treated with NaH(11 mg, 0.462 mmol), then 2-(chloromethyl)-oxazole (54 mg, 0.46 mmol)followed by stirring at room temperature overnight. After workup, theproduct was purified by silica gel chromatography. ¹H NMR (CDCl₃, 300MHz) δ ppm 1.33 (s, 9H), 3.75 (s, 3H), 5.51 (s, 2H), 7.08 (d, 1H), 7.21(d, 1H), 7.42 (s, 1H), 7.44 (dd, 1H), 7.57 (d, 1H), 8.11 (d, 1H); MS(ESI⁺) m/z 406 (M+H)⁺.

Example 337N-[(2Z)-5-tert-butyl-3-(1,2,4-oxadiazol-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 244A and commercially available3-(chloromethyl)-1,2,4-oxadiazole (May bridge) were processed using themethod described in Example 266 to afford the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H), 3.74 (s, 3H), 5.59 (s, 2H), 7.08(d, J=9.2 Hz, 1H), 7.39-7.49 (m, 1H), 7.43 (s, 1H), 7.59 (d, J=2.7 Hz,1H), 9.63 (s, 1H); MS (ESI⁺) m/z 407 (M+H)⁺; Anal. Calculated forC₁₈H₁₉ClN₄O₃S: C, 53.13; H, 4.71; N, 13.77. Found: C, 53.14; H, 4.57; N,13.56.

Example 338N-[(2Z)-5-tert-butyl-3-(2-furylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 338A 5-tert-butyl-3-(furan-2-ylmethyl)thiazol-2(3H)-imine

Commercially available 3,3-dimethylbutanal (Aldrich),2-furan-2-ylmethanamine (Aldrich), potassium thiocyanate (Aldrich) andiodine (EMD chemicals) were processed using the method described inExample 315A to afford the title compound. MS (ESI⁺) m/z 237 (M+H)⁺.

Example 338B(Z)—N-(5-tert-butyl-3-(furan-2-ylmethyl)thiazol-2(3H)-ylidene)-5-chloro-2-methoxybenzamide

Example 338A and Example 205B were processed using the method describedin Example 244A to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ ppm 1.31 (s, 9H), 3.79 (s, 3H), 5.37 (s, 2H), 6.22-6.59 (m, 2H), 7.12(d, J=8.7 Hz, 1H), 7.30 (s, 1H), 7.46 (dd, J=8.9, 3.0 Hz, 1H), 7.65 (dd,J=1.8, 1.0 Hz, 1H), 7.73 (d, J=2.8 Hz, 1H); MS (ESI⁺) m/z 405 (M+H)⁺.

Example 3395-chloro-N-[(2Z)-4,5-dimethyl-3-[(3-methylisoxazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 339A 4,5-dimethyl-3-(prop-2-ynyl)thiazol-2(3H)-iminehydrobromide

To a solution of 4,5-dimethylthiazol-2-amine (2.5 g, 19.5 mmol) in 10 mLtoluene was added propargyl bromide (2.78 g, 23.4 mmol). The reactionwas heated at 85° C. for 12 h then cooled. The crude material wasdiluted with diethyl ether and the solid was collected via filtration togive 3.5 g of the title compound which was used without furtherpurification. m/z 167.1 (M+H)⁺.

Example 339B5-chloro-N-[(2Z)-4,5-dimethyl-3-prop-2-yn-1-yl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

To a solution of Example 339A (0.5 g, 2.03 mmol) in 15 mL acetonitrilewas added Example 205B (0.54 g, 2.69 mmol) and triethylamine (0.81 g,8.12 mmol). The reaction was heated at 65° C. for 6 h, then at roomtemperature overnight. The crude reaction was triturated with methylenechloride/hexane and the resulting solid collected. The filtrate waschromatographed over silica gel (gradient elution, 20-40% ethylacetate/hexane) and combined with the material from the aforementionedtrituration to give 0.3 g of the title compound. m/z 334.9 (M+H)⁻.

Example 339C5-chloro-N-[(2Z)-4,5-dimethyl-3-[(3-methylisoxazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

To a solution of acetaldehyde oxime (0.085 g, 2.24 mmol) in 10 mLchloroform was added N-chlorosuccinimide (0.27 g, 2 mmol) and a drop ofpyridine. The solution was stirred at ambient temperature for 4 h whenExample 339B (0.15 g, 0.45 mmol) and triethylamine (0.224 g, 2.24 mmol)were added. The reaction was held at ambient temperature overnight, thendiluted with ethyl acetate, washed with water, brine, dried over MgSO₄,filtered, and concentrated. The material was purified by flashchromatography over silica gel (50% ethyl acetate/hexane) to give 0.075g of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.20 (s, 3H)2.23 (s, 3H) 2.26 (s, 3H) 3.77 (s, 3H) 5.57 (s, 2H) 6.28 (s, 1H) 7.10(d, J=9.15 Hz, 1H) 7.34-7.59 (m, 1H) 7.69 (d, J=2.71 Hz, 1H). m/z 392.0(M+H)⁺.

Example 3405-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-thiazol-2(3H)-ylidene]benzamideExample 340A 5-chloro-2-methoxy-N-(5-methylthiazol-2-yl)benzamide

To a solution of 5-methylthiazol-2-amine (0.25 g, 2.25 mmol) in 15 mLacetonitrile was added Example 205B (0.5 g, 2.7 mmol) and triethylamine(0.45 g, 4.5 mmol). The reaction was heated at reflux for 4 h and then65° C. overnight. The reaction was cooled, diluted with ethyl acetateand washed with NaHCO₃, brine, dried over MgSO₄, filtered, andconcentrated to give 0.4 g of the crude title compound, which was usedwithout further purification. m/z 282.9 (M+H)⁺.

Example 340B5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of Example 340A (0.1 g, 0.36 mmol) in 5 mL DMF was addedsodium hydride (0.01 g, 0.39 mmol, 95%). The solution was allowed tostir at ambient temperature for 30 min when2-(bromomethyl)-5-(trifluoromethyl)furan (0.09 g, 0.39 mmol) was added.The reaction was held at ambient temperature overnight and then quenchedwith water. The crude was extracted with ethyl acetate and the organicswashed with water, then dried over MgSO₄, filtered, and concentrated.Flash chromatography over silica gel (50% ethyl acetate/hexane) gave0.05 g of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.28 (d,J=1.36 Hz, 3H) 3.78 (s, 3H) 5.47 (s, 2H) 6.66 (d, J=2.71 Hz, 1H) 7.11(d, J=8.81 Hz, 1H) 7.22 (dd, J=3.39, 1.36 Hz, 1H) 7.31-7.39 (m, J=1.36Hz, 1H) 7.41-7.52 (m, 1H) 7.72 (d, J=2.71 Hz, 1H). m/z 431.0 (M+H)⁺.

Example 3415-chloro-N-[(2Z)-3-(2-furylmethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

To a solution of Example 340A (0.15 g, 0.53 mmol) in 5 mL DMF was addedsodium hydride (0.016 g, 0.67 mmol, 95%). After the solution was allowedto stir at ambient temperature for 30 min, 2-(chloromethyl)furan (0.08g, 0.67 mmol) was added. The reaction was held at ambient temperatureovernight and then quenched with water. The crude was extracted withethyl acetate and the organics washed with water, then dried over MgSO₄,filtered, and concentrated. Flash chromatography over silica gel (50%ethyl acetate/hexane) gave 0.075 g of the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.26 (d, J=1.36 Hz, 3H) 3.80 (s, 3H) 5.18 (s, 2H)6.54 (s, 1H) 7.12 (d, J=8.81 Hz, 1H) 7.29 (d, J=1.36 Hz, 1H) 7.46 (dd,J=8.81, 2.71 Hz, 1H) 7.64 (t, J=1.70 Hz, 1H) 7.67-7.76 (m, 2H). m/z363.0 (M+H)⁺.

Example 3425-chloro-N-[(2Z)-3-(3-furylmethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

To a solution of Example 340A (0.15 g, 0.53 mmol) in 5 mL DMF was addedsodium hydride (0.016 g, 0.67 mmol, 95%). After the solution was allowedto stir at ambient temperature for 30 min, 3-(chloromethyl)furan (0.08g, 0.67 mmol) was added. The reaction was held at ambient temperatureovernight and then quenched with water. The crude was extracted withethyl acetate and the organics washed with water, then dried over MgSO₄,filtered, and concentrated. Flash chromatography over silica gel (50%ethyl acetate/hexane) gave 0.035 g of the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.27 (d, J=1.36 Hz, 3H) 3.80 (s, 3H) 5.38 (s, 2H)6.39-6.55 (m, 2H) 7.12 (d, J=8.82 Hz, 1H) 7.26 (d, J=1.36 Hz, 1H) 7.46(dd, J=8.82, 2.71 Hz, 1H) 7.64 (s, 1H) 7.75 (d, J=2.71 Hz, 1H). m/z363.0 (M+H)⁺.

Example 343N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-ethoxy-5-(trifluoromethyl)benzamideExample 343AN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-fluoro-5-(trifluoromethyl)benzamide

To the product of Example 240C (0.62 g, 1.5 mmol) in THF (15 mL) wasadded triethylamine (1.1 mL, 7.7 mmol) followed by2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.39 mL, 2.6 mmol). Thismixture was warmed to 50° C. and was allowed to stir for 4 h. Themixture was cooled to ambient temperature then was quenched withsaturated, aqueous NH₄Cl (5 mL) and was diluted with EtOAc (5 mL). Thelayers were separated and the aqueous layer was extracted with EtOAc(3×5 mL). The combined organics were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The crude material waspurified by column chromatography (SiO₂, 60% hexanes in EtOAc) to givethe title compound (0.44 g, 1.0 mmol, 66% yield). MS (DCI/NH₃) m/z 431(M+H)⁺.

Example 343BN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-ethoxy-5-(trifluoromethyl)benzamide

To ethanol (0.13 mL, 2.15 mmol) in 5 mL THF was added potassiumtert-butoxide (0.23 g, 2.0 mmol). The mixture was stirred at ambienttemperature for 20 min then the product of Example 343A (0.44 g, 1.0mmol) in THF (10 mL) was added via cannula. The mixture was stirred for1 h at ambient temperature then was quenched with saturated, aqueousNH₄Cl (5 mL) and was diluted with EtOAc (5 mL). The layers wereseparated, the aqueous layer was extracted with EtOAc (3×5 mL) and thecombined organics were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography (SiO₂, 60% hexanes in EtOAc) to give the titlecompound (0.45 g, 0.99 mmol, 96% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 9H), 1.48 (t, J=7.0 Hz, 3H), 1.62-1.77 (m, 1H), 1.76-1.95 (m,2H), 1.99-2.12 (m, 1H), 3.73-3.90 (m, 2H), 4.16-4.24 (m, 3H), 4.29 (dt,J=13.1, 6.7, 2.5 Hz, 1H), 4.42 (dd, J=13.6, 3.1 Hz, 1H), 6.86 (s, 1H),7.01 (d, J=8.5 Hz, 1H), 7.59 (dd, J=9.0, 2.2 Hz, 1H), 8.24 (d, J=2.4 Hz,1H); MS (DCI/NH3) m/z 457 (M+H)+. Anal. Calculated for C₂₂H₂₇F₃N₂O₃S;Calc: C, 57.88; H, 5.96; N, 6.14. Found: C, 57.91; H, 5.91; N, 6.10.

Example 3445-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(2-morpholin-4-ylethyl)-1,3-thiazol-2(3H)-ylidene]benzamideExample 344A 5-methyl-3-(2-morpholinoethyl)thiazol-2(3H)-imine

A mixture of 2-amino-5-methylthiazole (1.0 g, 8.8 mmol),4-(2-chloroethyl)-morpholine hydrochloride (1.7 g, 9.2 mmol) and Et₃N(3.7 mL, 26 mmol) in DMF (5 mL) was warmed to 80° C. and was allowed tostir for 24 h. The mixture was then cooled to ambient temperature,quenched with saturated aqueous NaHCO₃ (5 mL), and diluted with CH₂Cl₂(5 mL). The layers were separated and the aqueous layer was extractedwith CH₂Cl₂ (3×5 mL). The combined organics were dried over anhydrousNa₂SO₄, filtered, concentrated under reduced pressure and purified viacolumn chromatography (SiO₂, 10% CH₃OH in EtOAc then 9:1:0.1CH₂Cl₂:CH₃OH:NH₄OH) to give the title compound (0.88 g, 3.9 mmol, 44%yield). MS (DCI/NH₃) m/z 228 (M+H)⁺.

Example 344B5-chloro-2-methoxy-N-[(2Z)-5-methyl-3-(2-morpholin-4-ylethyl)-1,3-thiazol-2(3H)-ylidene]benzamide

To a solution of the product of Example 344A (0.15 g, 0.66 mmol) in THF(10 mL) was added Et₃N (0.28 mL, 2.0 mmol) followed by Example 205B(0.66 mmol) in 5 mL THF via cannula. This mixture was warmed to 50° C.and was stirred for 4 h. The mixture was cooled to ambient temperature,was quenched with saturated, aqueous NaHCO₃ (5 mL) and was diluted withEtOAc (5 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (3×5 mL). The combined organics were dried overanhydrous Na₂SO₄, filtered, concentrated under reduced pressure andpurified via column chromatography (SiO₂, 9:1:0.1 CH₂Cl₂:CH₃OH:NH₄OH) togive the title compound (0.16 g, 0.39 mmol, 59% yield). ¹H NMR (300 MHz,CD₃OD) δ ppm 2.34 (d, J=1.4 Hz, 3H), 2.59-2.65 (m, 4H), 2.86 (t, J=6.4Hz, 2H), 3.59-3.67 (m, 4H), 3.86 (s, 3H), 4.40 (t, J=6.3 Hz, 2H), 7.08(d, J=8.8 Hz, 1H), 7.16 (d, J=1.4 Hz, 1H), 7.40 (dd, J=8.8, 2.7 Hz, 1H),7.85 (d, J=3.1 Hz, 1H); MS (DCI/NH3) m/z 396 (M+H)⁺. Anal. Calculatedfor C₁₈H₂₂ClN₃O₃S.0.5H₂O; Calc: C, 53.39; H, 5.73; N, 10.38. Found: C,53.62; H, 5.33; N, 10.00.

Example 345N-[(2Z)-5-tert-butyl-3-{[(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A mixture of Example 244A (180 mg, 0.55 mmol),(S)-(2-oxo-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate (180 mg, 0.67mmol), potassium carbonate (153 mg, 1.1 mmol), tetrabutylammonium iodide(10 mg, 0.03 mmol), tetrabutylammonium hydrogen sulfate (10 mg, 0.03mmol) and tetraethylammonium iodide (10 mg, 0.04 mmol) in toluene (35mL) was refluxed for 14 h. The mixture was washed with water, brine,dried with MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by chromatography over silica gel (EtOAc as eluent)to afford 100 mg of the title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 9H), 3.92 (s, 3H), 4.11-4.26 (m, 2H), 4.30-4.41 (m, 2H), 4.57(t, J=8.6 Hz, 1H), 6.33 (s, 1H), 6.62 (s, 1H), 6.93 (d, J=8.8 Hz, 1H),7.35 (dd, J=9.0, 2.9 Hz, 1H), 7.79 (d, J=2.7 Hz, 1H). MS (DCI/NH₃) m/z424 (M+H)⁺.

Example 3462-[(1-aminocyclopentyl)methoxy]-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

A mixture of Example 343A (215 mg, 0.5 mmol),(1-aminocyclopentyl)methanol (115 mg, 1.0 mmol) and potassiumtert-butoxide (1N solution in THF) (0.75 mL, 0.75 mmol) in THF (15 mL)was stirred at room temperature for 2 h. The mixture was then acidifiedto pH 5 with acetic acid and concentrated under reduced pressure. Theresidue was treated with a saturated solution of NaHCO₃ and extractedwith ethyl acetate. The organic layer was washed with brine, dried withMgSO₄, filtered, and concentrated under reduced pressure. The residuewas purified by chromatography over silica gel (EtOAc-MeOH 4:1 aseluent) to afford 175 mg of the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.32 (s, 9H), 1.37-2.08 (m, 14H), 3.59-3.66 (m, 1H), 3.77(t, J=7.3 Hz, 1H), 3.92 (s, 2H), 4.15-4.35 (m, 3H), 7.20-7.32 (m, 2H),7.74 (dd, J=8.7, 2.4 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H). MS (DCI/NH₃) m/z526 (M+H)⁺. Anal. calculated for C₂₆H₃₄F₃N₃O₃S: C, 59.41; H, 6.52; N,7.99. Found: C, 59.37; H, 6.74; N, 7.60.

Example 347N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(3S)-1-(2-oxopropyl)pyrrolidin-3-yl]oxy}-5-(trifluoromethyl)benzamideExample 347AN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(3S)-pyrrolidin-3-yloxy]-5-(trifluoromethyl)benzamide

A mixture of Example 343A (860 mg, 2 mmol), (S)-pyrrolidin-3-ol (348 mg,4.0 mmol) and potassium tert-butoxide (1N solution in THF) (3 mL, 3mmol) in THF (15 mL) was stirred at room temperature for 1 h. Themixture was then acidified to pH 5 with acetic acid and concentratedunder reduced pressure. The residue was treated with a saturatedsolution of NaHCO₃ and extracted with ethyl acetate. The organic layerwas washed with brine, dried with MgSO₄, filtered, and concentratedunder reduced pressure to afford 950 mg of the crude title compound. MS(DCI/NH₃) m/z 498 (M+H)⁺.

Example 347BN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(3S)-1-(2-oxopropyl)pyrrolidin-3-yl]oxy}-5-(trifluoromethyl)benzamide

To a mixture of Example 347A (400 mg, 0.8 mmol) and K₂CO₃ (222 mg, 1.6mmol) in acetonitrile (35 mL) was added at ambient temperature1-chloropropan-2-one (91 mg, 1 mmol) and the resulting mixture wasstirred at room temperature for 15 h. The mixture was concentrated underreduced pressure, the residue was dissolved in EtOAc, washed with water,brine, dried with MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by chromatography (EtOAc-MeOH 9:1 aseluent) to afford 370 mg of the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.29-1.36 (m, 9H), 1.58-1.67 (m, 1H), 1.71-1.98 (m, 6H),2.04 (s, 3H), 2.21-2.35 (m, J=13.6, 6.4 Hz, 1H), 2.53-2.59 (m, J=6.4 Hz,1H), 2.65-2.77 (m, 2H), 3.01 (dd, J=10.3, 6.3 Hz, 1H), 3.60-3.71 (m,1H), 3.73-3.83 (m, 1H), 4.14-4.35 (m, 3H), 4.94-5.07 (m, 1H), 7.16-7.30(m, 2H), 7.72 (dd, J=8.8, 2.0 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H). MS(DCI/NH₃) m/z 554 (M+H)⁺.

Example 348N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-({1-[2-(hydroxyimino)propyl]azetidin-3-yl}oxy)-5-(trifluoromethyl)benzamideExample 348AN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[1-(2-oxopropyl)azetidin-3-yl]oxy}-5-(trifluoromethyl)benzamide

To a mixture of Example 382B (485 mg, 1 mmol) and K₂CO₃ (348 mg, 2.5mmol) in acetonitrile (35 mL) was added at ambient temperature1-chloropropan-2-one (139 mg, 1.5 mmol) and the resulting mixture wasstirred at room temperature for 16 h. The mixture was concentrated underreduced pressure, the residue was dissolved in EtOAc, washed with water,brine, dried with MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by chromatography (CH₂Cl₂-MeOH 9:1 aseluent) to afford 200 mg of the title compound. MS (DCI/NH₃) m/z 540(M+H)⁺.

Example 348BN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-({1-[2-(hydroxyimino)propyl]azetidin-3-yl}oxy)-5-(trifluoromethyl)benzamide

A mixture of Example 348A (162 mg, 0.3 mmol) and hydroxylaminehydrochloride (31 mg, 0.45 mmol) in pyridine (10 mL) was stirred at roomtemperature for 14 h and then was concentrated under reduced pressure. Asaturated solution of sodium bicarbonate was added to the residue andthe mixture was extracted with ethyl acetate. The ethyl acetate extractwas washed with water, brine, dried with MgSO₄, filtered, andconcentrated under reduced pressure. Purification by silica gelchromatography (Ethyl acetate-MeOH 9:1) afforded 60 mg of the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H), 1.58-2.00 (m,7H), 3.00-3.04 (m, 2H), 3.10 (s, 2H), 3.62-3.85 (m, 4H), 4.19-4.39 (m,3H), 4.94 (t, J=5.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 7.22-7.33 (m, 1H),7.70 (dd, J=8.5, 2.0 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 10.52 (s, 1H). MS(DCI/NH₃) m/z 555 (M+H)⁺.

Example 3495-chloro-2-(4-chlorophenoxy)-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamideExample 349A5-chloro-2-fluoro-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide

Example 140A and 5-chloro-2-fluorobenzoic acid were processed using themethod described in Example 223A to afford the title compound. MS (ESI)m/z 329 (M+H)⁺.

Example 349B5-chloro-2-(4-chlorophenoxy)-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]benzamide

Example 349A and 4-chlorophenol were processed using the methoddescribed in Example 280B to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.25 (s, 3H) 3.18 (s, 3H) 3.44 (t, J=5.22 Hz, 2H) 4.06(t, J=5.22 Hz, 2H) 6.87-6.94 (m, 2H) 7.10 (d, J=8.90 Hz, 1H) 7.18 (d,J=1.53 Hz, 1H) 7.33-7.40 (m, 2H) 7.56 (dd, J=8.59, 2.76 Hz, 1H) 7.91 (d,J=2.76 Hz, 1H); MS (ESI) m/z 437 (M+H)⁺.

Example 3505-chloro-N-[(2Z)-3-(2-methoxyethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene]-2-(tetrahydrofuran-3-yloxy)benzamide

Example 349A and tetrahydrofuran-3-ol were processed using the methoddescribed in Example 280B to afford the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.93-2.00 (m, 1H) 2.12-2.21 (m, 1H) 2.28 (s, 3H) 3.26 (s,3H) 3.68 (t, J=5.19 Hz, 2H) 3.70-3.75 (m, 1H) 3.75-3.84 (m, 2H) 3.88(dd, J=10.07, 4.88 Hz, 1H) 4.32 (t, J=5.19 Hz, 2H) 5.02-5.07 (m, 1H)7.09 (d, J=8.85 Hz, 1H) 7.24 (d, J=1.22 Hz, 1H) 7.42 (dd, J=8.85, 2.75Hz, 1H) 7.68 (d, J=2.75 Hz, 1H); MS (ESI) m/z 397 (M+H)⁺.

Example 351N-[(2Z)-5-tert-butyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-fluoro-3-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure described inExamples 319A and 319B, replacing Example 205B with2-fluoro-3-(trifluoromethyl)benzoyl chloride in 67.7% yield. ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.39 (s, 9H), 1.58-2.05 (m, 4H), 2.44 (s, 3H), 3.63(q, J=7.54 Hz, 1H), 3.72-3.84 (m, 1H), 4.07-4.21 (m, 1H), 4.22-4.34 (m,1H), 4.42 (dd, J=13.88, 2.78 Hz, 1H), 7.45-7.52 (m, 1H), 7.84-7.94 (m,1H), 8.19-8.34 (m, 1H); MS (ESI) m/z 445 [M+H]⁺, 443 [M−H].

Example 352N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(dimethylamino)ethoxy]-5-(trifluoromethyl)benzamide

To a solution of 2-(dimethylamino)ethanol (89 mg, 1.0 mmol) in THF (2mL) was added potassium tert-butoxide 1.0M solution in THF (1 mL). Themixture was stirred at room temperature for 10 min and then Example 372B(215 mg, 0.5 mmol) was added and stirred at room temperature for another2 hrs. The reaction mixture was quenched with saturated aqueous ammoniumchloride and extracted by ethyl acetate (3×10 mL). The combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated. Purification by column chromatography eluting withNH₃/MeOH (1:9) in 5-30% gradient in ethyl acetate afforded the titlecompound (190 mg, 76%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.32 (s, 9H),1.57-2.01 (m, 4H), 2.36-2.46 (m, 6H), 2.90 (s, 2H), 3.59-3.84 (m, 2H),4.17-4.35 (m, 5H), 7.26-7.37 (m, 2H), 7.77 (dd, J=8.72, 1.98 Hz, 1H),8.00 (d, J=2.38 Hz, 1H); MS (ESI) m/z 500 [M+H]⁺.

Example 353N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(dimethylamino)-2-methylpropoxy]-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure described inExample 352, replacing 2-(dimethylamino)ethanol with2-(dimethylamino)-2-methylpropan-1-ol in 80% yield. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.10 (s, 6H), 1.29-1.40 (m, 9H), 1.55-1.69 (m, 1H),1.73-1.97 (m, 3H), 2.06-2.34 (m, 6H), 3.59-3.68 (m, 1H), 3.73-3.83 (m,1H), 3.94 (s, 2H), 4.15-4.31 (m, 3H), 7.21-7.37 (m, 2H), 7.73 (d, J=9.12Hz, 1H), 7.95 (s, 1H); MS (ESI) m/z 528 [M+H]⁺.

Example 354N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(2-morpholin-4-ylethoxy)-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure described inExample 352, replacing 2-(dimethylamino)ethanol with 2-morpholinoethanolin 85% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.32 (s, 9H), 1.57-1.69(m, 1H), 1.73-1.94 (m, 3H), 2.36-2.48 (m, 4H), 2.69 (t, J=5.93 Hz, 2H),3.45-3.57 (m, 4H), 3.58-3.71 (m, 1H), 3.72-3.85 (m, 1H), 4.12-4.37 (m,5H), 7.22-7.34 (m, 2H), 7.73 (dd, J=8.82, 2.03 Hz, 1H), 7.92 (d, J=2.37Hz, 1H); MS (ESI) m/z 542 [M+H]⁺.

Example 355 N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(diethylamino)ethoxy]-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure described inExample 352, replacing 2-(dimethylamino)ethanol with2-(diethylamino)ethanol in 82% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.73-1.19 (m, 6H), 1.32 (s, 9H), 1.55-2.02 (m, 4H), 2.49-2.67 (m, 4H),2.69-2.98 (m, 2H), 3.58-3.84 (m, 2H), 3.92-4.55 (m, 5H), 7.14-7.41 (m,2H), 7.75 (s, 1H), 7.95 (s, 1H); MS (ESI) m/z 528 [M+H]⁺.

Example 356N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(1,1-dioxidothiomorpholin-4-yl)ethoxy]-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure described inExample 352, replacing 2-(dimethylamino)ethanol with4-(2-hydroxyethyl)thiomorpholine-1,1-dioxide in 80% yield. ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.32 (s, 9H), 1.55-2.01 (m, 4H), 2.93 (t, J=5.55 Hz,2H), 2.96-3.10 (m, 8H), 3.60-3.68 (m, 1H), 3.72-3.82 (m, 1H), 4.11-4.36(m, 5H), 7.24-7.33 (m, 2H), 7.75 (dd, J=8.92, 2.58 Hz, 1H), 7.95 (d,J=2.38 Hz, 1H); MS (ESI) m/z 590 [M+H]⁺.

Example 357N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(2-piperidin-1-ylethoxy)-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure described inExample 352, replacing 2-(dimethylamino)ethanol with2-(piperidin-1-yl)ethanol in 69% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.32 (s, 9H), 1.33-1.39 (m, 2H), 1.39-1.49 (m, 4H), 1.57-1.70 (m, 1H),1.74-1.86 (m, 2H), 1.86-1.98 (m, 1H), 2.36-2.46 (m, 4H,) 2.65 (t, J=6.35Hz, 2H), 3.61-3.70 (m, 1H), 3.74-3.83 (m, 1H), 4.15-4.23 (m, 4H),4.24-4.33 (m, 1H), 7.25 (s, 1H), 7.30 (d, J=9.12 Hz, 1H), 7.73 (dd,J=8.73, 2.38 Hz, 1H), 7.92 (d, J=2.38 Hz, 1H); MS (+DCI) m/z 540 [M+H]⁺.

Example 358N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(3-methoxy-3-methylbutoxy)-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure described inExample 352, replacing 2-(dimethylamino)ethanol with3-methoxy-3-methylbutan-1-ol in 55% yield. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.15 (s, 6H), 1.32 (s, 9H), 1.58-1.70 (m, 1H), 1.75-1.98 (m, 5H),3.10 (s, 3H), 3.60-3.70 (m, 1H), 3.73-3.83 (m, 1H), 4.10-4.35 (m, 5H),7.23-7.32 (m, 2H), 7.73 (dd, J=8.72, 2.38 Hz, 1H), 7.94 (d, J=2.38 Hz,1H); MS (+DCI) m/z 529 [M+H]⁺.

Example 359N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(2-oxopyrrolidin-1-yl)ethoxy]-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure described inExample 352, replacing 2-(dimethylamino)ethanol with1-(2-hydroxyethyl)pyrrolidin-2-one in 35% yield. ¹H NMR (300 MHz,DMSO-d₆) δ ppm) δ ppm 1.32 (s, 9H) 1.54-1.97 (m, 6H) 2.11-2.22 (m, 2H)3.43 (t, J=6.95 Hz, 2H) 3.52 (t, J=5.43 Hz, 2H) 3.59-3.70 (m, 1H)3.72-3.83 (m, 1H) 4.13-4.34 (m, 5H) 7.23-7.33 (m, 2H) 7.74 (dd, J=8.82,2.03 Hz, 1H) 7.93 (d, J=2.03 Hz, 1H); MS (+DCI) m/z 540 [M+H]⁺.

Example 3601-benzyl-3-tert-butyl-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-1H-pyrazole-5-carboxamide

To a solution of Example 372A (737 mg, 2.0 mmol) and triethylamine (1.4mL, 10.0 mmol) in dichloromethane (10 mL) was added1-benzyl-3-(tert-butyl)-1H-pyrazole-5-carbonyl chloride (720 mg, 1.3mmol) dropwise. The mixture was stirred at room temperature for 2 hr,and then water (10 mL) was added. The reaction mixture was extractedwith dichloromethane (10 mL×2). The combined organic layer was washedwith brine, dried over magnesium sulfate and concentrated. The residuewas purified by column chromatography over silica gel eluting with ethylacetate in hexane in 5-30% gradient to provide the title compound (680mg, 70.7% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.26 (s, 9H), 1.29 (s,9H), 1.46-1.60 (m, 1H), 1.70-1.92 (m, 3H), 3.57-3.66 (m, 1H), 3.70-3.80(m, 1H), 4.12-4.24 (m, 3H), 5.79-5.92 (m, 2H), 6.77 (s, 1H), 7.06 (d,J=7.14 Hz, 2H), 7.18-7.33 (m, 4H); MS (+ESI) m/z 526 [M+H]⁺.

Example 361 methyl2-({[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-4-(trifluoromethyl)benzoate

To Example 386B (2.6 g, 5.29 mmol) and MeOH (50 mL) in a 250 mLstainless steel pressure bottle was added Pd-dppf (Heraeus) (0.194 g,0.265 mmol) and triethylamine (1.475 mL, 10.58 mmol). The mixture waspressurized with carbon monoxide (60 psi) and stirred at 95° C. for 16hrs. The reaction mixture was concentrated to dryness and purified bycolumn chromatography over silica gel eluting with ethyl acetate inhexane in 5-30% gradient to provide the title compound (2.3 g, 92%yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H), 1.52-2.02 (m, 4H),3.60-3.69 (m, 1H), 3.73-3.83 (m, 4H), 4.14-4.34 (m, 3H), 7.32 (s, 1H),7.89 (s, 1H), 7.96 (d, J=8.33 Hz, 1H), 8.16 (d, J=7.93 Hz, 1H); MS(+ESI) m/z 526 [M+H]⁺.

Example 3623-tert-butyl-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-1-methyl-1H-pyrazole-5-carboxamide

The title compound was prepared according to the procedure described inExample 360, replacing 1-benzyl-3-(tert-butyl)-1H-pyrazole-5-carbonylchloride with 3-tert-butyl-1-methyl-1H-pyrazole-5-carbonyl chloride in79% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.25 (s, 9H) 1.31 (s, 9H)1.56-2.04 (m, 4H) 3.59-3.70 (m, 1H) 3.73-3.84 (m, 1H) 4.10 (s, 3H)4.19-4.33 (m, 3H) 6.67 (s, 1H) 7.26 (s, 1H); MS (+ESI) m/z 417 [M+H]⁺.

Example 363N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

The mixture of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (234 mg, 1.2 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (383 mg, 1.5 mmol) in DMF (4 mL) was stirred at room temperaturefor 10 min, and then Example 372A (241 mg, 1.0 mmol) was added, followedby triethylamine (0.14 mL, 0.1 mmol) dropwise. The mixture was stirredfor another 2 hrs and monitored by LC/MS. Water (10 mL) and ethylacetate (20 mL) were added and the organic layer was washed withsaturated NaHCO₃ and brine and concentrated. Purification by columnchromatography over silica gel eluting with ethyl acetate in hexane in5-40% gradient yielded the title compound (340 mg, 82% yield). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.32 (s, 9H), 1.55-2.05 (m, 4H), 3.58-3.71 (m,1H), 3.72-3.83 (m, 1H), 4.26 (s, 3H), 4.27-4.33 (m, 3H), 7.23 (s, 1H),7.33 (s, 1H); MS (+ESI) m/z 417 [M+H]⁺.

Example 3642-[2-(tert-butylamino)ethoxy]-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

The title compound was prepared according to the procedure described inExample 352, replacing 2-(dimethylamino)ethanol with2-(tert-butylamino)ethanol in 89% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.96-1.18 (m, 9H), 1.32 (s, 9H), 1.56-2.02 (m, 4H), 2.89 (s, 2H),3.59-3.70 (m, 1H), 3.72-3.84 (m, 1H), 4.08-4.35 (m, 5H), 7.25-7.39 (m,2H), 7.77 (dd, J=8.81, 2.03 Hz, 1H), 8.01 (s, 1H); MS (+ESI) m/z 528[M+H]⁺.

Example 365 tert-butyl3-{[3-tert-butyl-5-({[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-pyrazol-1-yl]methyl}azetidine-1-carboxylateExample 365A3-tert-butyl-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-1H-pyrazole-5-carboxamide

To Example 360 (600 mg, 1.248 mmol) and ethanol (5 mL) in a 20 mLpressure bottle was added 20% Pd(OH)₂/C, wet (300 mg, 2.135 mmol) andhydrochloric acid (0.208 mL, 2.497 mmol). The mixture was stirred at 50°C. under hydrogen (60 psi) for 2.5 days. HPLC analysis showed conversioncompleted. The mixture was, filtered, and concentrated to dryness toafford the title compound (450 mg, 92% yield). LC/MS (TFA-method) 391[M+H]⁺.

Example 365B tert-butyl3-{[3-tert-butyl-5-({[2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-pyrazol-1-yl]methyl}azetidine-1-carboxylate

Example 365A (155 mg, 0.397 mmol), potassium tert-butoxide (89 mg, 0.794mmol), and tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (142 mg,0.476 mmol) in dimethylacetamide (4 mL) were reacted at ambienttemperature for 2 hrs. The reaction was quenched with saturated NaHCO₃and diluted with ethyl acetate. The water layer was extracted with ethylacetate (10 mL×2). The combined organics were washed with brine anddried over MgSO₄, filtered, and concentrated. Purification by columnchromatography (silica gel, ethyl acetate in hexane in 5-40% gradient)provided the title compound (145 mg, 65.3% yield). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.31 (s, 9H), 1.35 (s, 9H), 1.43 (s, 9H), 1.61-2.14 (m,4H), 3.06-3.23 (m, 1H), 3.70-3.98 (m, 6H), 4.14-4.45 (m, 3H), 4.88 (t,J=6.95 Hz, 2H), 6.74 (s, 1H), 6.86 (s, 1H); MS (+ESI) m/z 560 [M+H]⁺.

Example 3661-(azetidin-3-ylmethyl)-3-tert-butyl-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-1H-pyrazole-5-carboxamide

A mixture of Example 365B (140 mg, 0.25 mmol) and 2,2,2-trifluoroaceticacid (0.193 mL, 2.5 mmol) in CH₂Cl₂ (5 mL) was stirred at roomtemperature overnight. The mixture was concentrated under reducedpressure and the residue was purified by HPLC on a Waters Symmetry C8column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10minutes run time) at a flow rate of 40 mL/minutes) to yield the titlecompound (78 mg, 67.8% yield) as a TFA salt. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.24-1.29 (m, 9H), 1.32 (s, 9H), 1.62-1.70 (m, 1H), 1.79-1.88 (m,2H), 1.92-2.02 (m, 1H), 3.20-3.34 (m, 1H), 3.66 (q, J=7.08 Hz, 1H),3.76-3.83 (m, 1H), 3.84-4.01 (m, 4H), 4.18-4.43 (m, 3H), 4.81 (d, J=6.92Hz, 2H), 6.74 (s, 1H), 7.29-7.31 (m, 1H), 8.63 (s, 1H); MS (+ESI) m/z460 [M+H]⁺.

Example 367N-[(2Z)-5-tert-butyl-3-[(5-methylisoxazol-3-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

A solution of Example 244A (275 mg, 0.84 mmol) in DMF at 0° C. wastreated with 60% NaH in mineral oil (40 mg, 1.03 mmol). After the gasevolution subsided, the reaction mixture was allowed to stir for 30 minand then treated with commercially available3-(chloromethyl)-5-methylisoxazole (111 mg, 0.847 mmol). The resultingmixture was stirred at room temperature for 18 hr, poured into brine andextracted with EtOAc. The organics were combined and washed with waterand brine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash chromatography over silica gel using 20% EtOAc inhexane to afford the title compound (165 mg, 37% yield). ¹H NMR (500MHz, DMSO-d₆) δ ppm 1.32 (s, 9H), 2.38 (s, 3H), 3.77 (s, 3H), 5.39 (s,2H), 6.23 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.39 (s, 1H), 7.45 (dd,J=9.0, 2.9 Hz, 1H), 7.65 (d, J=3.1 Hz, 1H). MS (DCI) m/z 420 (M+H)⁺.Elemental analysis calculated for C₂₀H₂₂ClN₃O₃S: C, 57.20; H, 5.28; N,10.01. Found: C, 57.16; H, 5.42; N, 9.75.

Example 368N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-({(3S)-1-[2-(hydroxyimino)propyl]pyrrolidin-3-yl}oxy)-5-(trifluoromethyl)benzamide

A solution of Example 347B (340 mg, 0.614 mmol) in pyridine (5 mL) wastreated with commercially available hydroxylamine hydrochloride (51 mg,0.73 mmol) and stirred at room temperature for 14 h. The reactionmixture was concentrated under reduced pressure and the residue waspartitioned between saturated sodium bicarbonate and ethyl acetate. Theorganic layer was washed with brine, dried with MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography over silica gel using EtOAc: MeOH (9:1) as eluent toafford the title compound (320 mg, 91% yield). ¹H NMR (300 MHz, DMSO-d₆)δ ppm 1.32 (s, 9H), 1.54-2.04 (m, 9H), 2.30 (dd, J=13.4, 6.6 Hz, 1H),2.41-2.75 (m, 3H), 2.91 (dd, J=10.2, 6.4 Hz, 1H), 3.06 (s, 1H),3.52-3.90 (m, 2H), 4.11-4.45 (m, 3H), 5.00 (s, 1H), 7.10-7.32 (m, 2H),7.71 (dd, J=8.6, 1.9 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 10.45 (s, 1H). MS(DCI) m/z 569 (M+H)⁺. Anal. calculated for C₂₇H₃₅F₃N₄O₄S.0.4H₂O: C,56.31; H, 6.27; N, 9.73; N. Found: C, 56.33; H, 6.39; N, 9.46.

Example 369N-[(2Z)-5-tert-butyl-3-(2-hydroxyethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamideExample 369A 2-(5-tert-butyl-2-iminothiazol-3(2H)-yl)ethanol

Commercially available 3,3-dimethylbutanal (Aldrich), 2-aminoethanol(Aldrich), potassium thiocyanate (Aldrich) and iodine (EMD chemicals)were processed using the method described in Example 315A to afford thetitle compound. MS (ESI⁺) m/z 201 (M+H)⁺.

Example 369BN-[(2Z)-5-tert-butyl-3-(2-hydroxyethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide

Example 369A and 5-chloro-2-methoxybenzoic acid (Aldrich) were processedusing the method described in Example 58 to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.32 (s, 9H), 3.71-3.83 (m, 2H), 3.78(s, 3H), 4.20 (t, J=5.4 Hz, 2H), 4.95 (t, 1H), 7.10 (d, J=8.8 Hz, 1H),7.23 (s, 1H), 7.44 (dd, J=8.8, 2.7 Hz, 1H), 7.62 (d, J=2.7 Hz, 1H); MS(ESI⁺) m/z 369 M+H)⁺, Anal. Calculated for C₁₇H₂₁ClN₂O₃S: C, 55.35; H,5.74; N, 7.59. Found: C, 55.02; H, 6.16; N, 7.28.

Example 3705-chloro-N-[(2Z)-5-(4,4-difluorocyclohexyl)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamideExample 370A (4,4-difluorocyclohexyl)methanol

To a suspension of lithium aluminum hydride (2.6 g, 69 mmol) in diethylether (160 mL) was added slowly a solution of commercially availableethyl 4,4-difluorocyclohexanecarboxylate (Matrix, 11.0 g, 57 mmol) indiethyl ether (20 mL). The reaction mixture was refluxed for 4 hours,then cooled in an ice bath, quenched cautiously with sequential additionof water (2.6 mL), 15% NaOH (2.6 mL) and water (7.8 mL) and extractedwith ethyl acetate (3×100 mL). The mixture was filtered and concentratedto afford the title compound.

Example 370B (4,4-difluorocyclohexyl)methyl 4-methylbenzenesulfonate

To a solution of Example 370A (8.5 g, 57 mmol) in dichloromethane (100mL) were added triethylamine (Aldrich, 25 mL, 180 mmol) and tosylchloride (Aldrich, 11.4 g, 60 mmol). The reaction mixture was stirred atroom temperature for 16 hours and washed with water (50 mL) and brine(50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography using an Analogix® Intelliflash280™ (SiO₂, 0-50% ethylacetate in hexanes) to afford the title compound. ¹H NMR (300 MHz,CDCl₃) δ ppm 1.17-1.42 (m, 2H), 1.57-1.69 (m, 1H), 1.70-1.91 (m, 4H),1.93-2.18 (m, 2H), 2.46 (s, 3H), 3.86 (d, J=6.4 Hz, 2H), 7.35 (d, J=8.5Hz, 2H), 7.78 (d, J=8.1 Hz, 2H).

Example 370C 2-(4,4-difluorocyclohexyl)acetonitrile

To a solution of Example 370B (4.5 g, 15 mmol) in dimethylsulfoxide (100mL) was added sodium cyanide (Aldrich, 2.2 g, 45 mmol). The reactionmixture was stirred at 80° C. for 14 hours, cooled to room temperature,quenched with saturated aqueous NaHCO₃ (50 mL) and extracted withdiethyl ether (3×50 mL). The combined organic extracts were dried overanhydrous MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography using an Analogix®Intelliflash280™ (SiO₂, 50% pentane in ether) to afford the titlecompound. MS (ESI⁺) m/z 177 (M+NH₄)⁺.

Example 370D 2-(4,4-difluorocyclohexyl)acetaldehyde

To a solution of Example 370C (3.8 g, 24 mmol) in dichloromethane (50mL) was added diisobutylaluminum hydride (1.6M in cyclohexane, 22.5 mL,36 mmol), dropwise. The reaction mixture was stirred at room temperaturefor 3 hours. The reaction mixture was quenched with 1M tartaric acid (40mL), stirred for 1 hour and the layers were separated. The aqueous layerwas extracted with dichloromethane (3×50 mL). The combined organicextracts were dried over anhydrous MgSO₄, filtered and concentratedunder reduced pressure to afford the title compound. MS (ESI⁺) m/z 162(M+NH₄—H₂O)⁺.

Example 370E 5-(4,4-difluorocyclohexyl)-2,3-dihydrothiazol-2-amine

Example 370D, pyrrolidine, p-toluenesulfonic acid monohydrate, sulfurand cyanamide were processed using the method described in Example 202Ato obtain the title compound. MS (ESI⁺) m/z 219 (M+H)⁺.

Example 370F5-(4,4-difluorocyclohexyl)-3-(2-methoxyethyl)thiazol-2(3H)-iminehydrobromide

A mixture of Example 370E and commercially available 2-bromoethyl methylether (Aldrich) was processed using the method described in Example 12Ato afford the title compound. MS (ESI⁻) m/z 277 (M+H)⁺.

Example 370G5-chloro-N-[(2Z)-5-(4,4-difluorocyclohexyl)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide

Example 370F and 5-chloro-2-methoxybenzoic acid (Aldrich) were processedusing the method described in Example 58 to afford the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.44-1.76 (m, 2H), 1.80-2.21 (m, 6H),2.80-2.99 (m, 1H), 3.26 (s, 3H), 3.72 (t, J=5.4 Hz, 2H), 3.78 (s, 3H),4.32 (t, J=5.3 Hz, 2H), 7.11 (d, J=9.2 Hz, 1H), 7.34 (s, 1H), 7.45 (dd,J=8.8, 3.1 Hz, 1H), 7.65 (d, J=2.7 Hz, 1H); MS (ESI⁺) m/z 445 (M+H)⁻,Anal. Calculated for C₂₀H₂₃ClF₂N₂O₃S: C, 53.99; H, 5.21; N, 6.30. Found:C, 54.03; H, 5.19; N, 6.27.

Example 371N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-cyano-5-(trifluoromethyl)benzamide

A mixture of Example 343A (180 mg, 0.42 mmol) and sodium cyanide (41.0mg, 0.84 mmol) in 0.4 mL of DMSO was heated at 120° C. for 2 h. Thereaction was cooled to room temperature and diluted with ether. Themixture was washed with brine, and the layers were separated. Theaqueous layer was extracted with ether (2×10 mL). The combined organicextracts were dried (MgSO₄), filtered, and concentrated. The residue waspurified by column chromatography using an Analogix® Intelliflash280™(SiO₂, 0-50% ethyl acetate in hexanes) to afford the title compound. ¹HNMR (300 MHz, CDCl₃) δ ppm 1.38 (s, 9H), 1.58-1.72 (m, 1H), 1.73-1.95(m, 2H), 2.09-2.23 (m, 1H), 3.73-3.89 (m, 2H), 4.25-4.39 (m, 2H),4.65-4.79 (m, 1H), 6.98 (s, 1H), 7.78 (dd, J=8.0, 1.9 Hz, 1H), 7.90 (d,J=7.9 Hz, 1H), 8.69 (d, J=1.6 Hz, 1H); MS (ESI⁺) m/z 438 (M+H)⁺.

Example 3722-tert-butoxy-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamideExample 372A5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-iminehydroiodide

To a solution of 3,3-dimethylbutanal (9.90 g, 99 mmol) in acetonitrile(60 mL) were added molecular sieves (8 g) and(R)-(tetrahydrofuran-2-yl)methanamine (10 g, 99 mmol). The reactionmixture was stirred at room temperature for 24 hr and then filtered. Tothe filtrate was added potassium thiocyanate (12.78 g, 131 mmol). Thetemperature was adjusted to 50° C. and the mixture was stirred until thesolids were dissolved. Then, iodine (25.09 g, 99 mmol) was added to themixture and stirred at 50° C. for 24 hr. The reaction mixture wascooled, and to the mixture was added sodium metabisulfite (20%, 100 mL)and stirred for 30 min. The organic layer was separated. The aqueouslayer was washed with dichloromethane (3×40 mL). The combined organicextracts were dried with sodium sulfate, filtered and concentrated toobtain the crude product as a yellow solid. The residue was taken intodichloromethane (20 mL) and ethyl acetate (80 mL) was added, the mixturewas warmed to 40° C., sonicated, and left in the refrigerator overnight.The solid was collected and washed with cold ethyl acetate to obtain thetitle compound as a white solid (18.2 g, 50%). ¹H NMR (300 MHz, DMSO-d₆)δ ppm 1.27 (s, 9H) 1.48-1.61 (m, 1H) 1.78-1.93 (m, 2H) 1.94-2.07 (m, 1H)3.62-3.71 (m, 1H) 3.76-3.84 (m, 1H) 3.92-4.08 (m, 2H) 4.11-4.20 (m, 1H)7.19 (s, 1H) 9.39 (s, 2H); MS (DCI/NH₃); m/z 241 (M+H)⁺.

Example 372BN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-fluoro-5-(trifluoromethyl)benzamide

In a 250 mL round-bottomed flask, Example 372A (6 g, 24.96 mmol) wasdissolved in dichloromethane (50 mL), triethylamine (8.70 mL, 62.4 mmol)was added followed by addition of 2-fluoro-5-(trifluoromethyl)benzoylchloride (3.78 mL, 24.96 mmol) dropwise and stirred for 2 hr. Thereaction was washed with water and dried with sodium sulfate. Thesolution was filtere and concentrated, and the residue was purified bycolumn chromatography using an Analogix® Intelliflash280™ (SiO₂, 0-30%ethyl acetate in hexane over 25 min) The product was concentrated toprovide the title compound as a viscous liquid (7.14 g, 66.4% yield). ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 1.62-1.72 (m, 1H) 1.78-1.88(m, 2H) 1.89-1.99 (m, 1H) 3.62-3.70 (m, 1H) 3.75-3.83 (m, 1H) 4.22-4.29(m, 2H) 4.29-4.37 (m, 1H) 7.34 (s, 1H) 7.48-7.57 (m, 1H) 7.86-7.97 (m,1H) 8.31 (dd, J=6.78, 2.37 Hz, 1H); MS (DCI/NH₃) m/z 431 (M+H)⁺.

Example 372C2-tert-butoxy-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

To a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 2 mL)was added Example 372B (163 mg, 0.38 mmol). The mixture was stirred atroom temperature overnight. The reaction was quenched with saturatedaqueous ammonium chloride and extracted by ethyl acetate (3×10 mL). Theorganic layers were combined, washed with water, dried, filtered, andconcentrated, and the residue was purified by column chromatographyusing an Analogix® Intelliflash280™ (SiO₂, 0-100% ethyl acetate inhexane) to afford the title compound (0.16 g, 80%). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.32 (s, 9H) 1.33 (s, 9H) 1.57-1.68 (m, 1H) 1.77-1.92 (m,3H) 3.60-3.68 (m, 1H) 3.78 (dt, J=8.39, 6.49 Hz, 1H) 4.17-4.22 (m, 2H)4.24-4.33 (m, 1H) 7.26 (s, 1H) 7.32 (d, J=8.48 Hz, 1H) 7.67 (dd, J=8.99,2.20 Hz, 1H) 7.88 (d, J=2.37 Hz, 1H); MS (DCI/NH₃) m/z 485 (M+H)⁺.

Example 373N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-5-(trifluoromethyl)benzamide

To a solution of (R)-1-methylpyrrolidin-3-ol (162 mg, 1.6 mmol) intetrahydrofuran (2 mL) was added sodium tert-butoxide (161 mg, 1.68mmol). The mixture was stirred at room temperature for 20 min before asolution of Example 372B (344 mg, 0.8 mmol) in tetrahydrofuran (1 mL)was added dropwise. The mixture was stirred at room temperature for 2 hrbefore it was quenched with saturated aqueous ammonium chloride andextracted by ethyl acetate (3×10 mL). The organic layers were combined,washed with brine, dried, filtered, concentrated and the residue waspurified by column chromatography using an Analogix® Intelliflash280™(SiO₂, gradient elution over 25 min with solvents A:B (100:0 to 10:90);solvent A=CH₂Cl₂; solvent B=7M NH₃/MeOH (1):CH₂Cl₂ (9)) to afford thetitle compound (150 mg, 37%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.32 (s,9H) 1.57-1.70 (m, 1H) 1.76-1.83 (m, 3H) 1.88-1.96 (m, 1H) 2.25 (s, 3H)2.29-2.44 (m, 2H) 2.60-2.73 (m, 2H) 2.78-2.84 (m, 1H) 3.61-3.69 (m, 1H)3.74-3.83 (m, 1H) 4.18-4.24 (m, 2H) 4.25-4.33 (m, 1H) 4.96-5.04 (m, 1H)7.18 (d, J=8.73 Hz, 1H) 7.26 (s, 1H) 7.72 (dd, J=8.73, 2.78 Hz, 1H) 7.96(d, J=2.78 Hz, 1H); MS (DCI/NH₃) m/z 512 (M+H)⁺. Anal. calcdC₂₄H₃₁F₃N₂O₃S: C, 58.69; H, 6.3; N, 8.21. Found: C, 58.58; H, 6.29; N,8.18.

Example 374N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-5-(trifluoromethyl)benzamide

The title compound was prepared and isolated as described in Example373, substituting (S)-1-methylpyrrolidin-3-ol for(R)-1-methylpyrrolidin-3-ol in 42% yield. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.31 (s, 9H) 1.58-1.69 (m, 1H) 1.74-1.85 (m, 3H) 1.87-1.98 (m, 1H)2.25 (s, 3H) 2.29-2.41 (m, 2H) 2.59-2.69 (m, 2H) 2.78-2.84 (m, 1H)3.60-3.69 (m, 1H) 3.74-3.83 (m, 1H) 4.18-4.32 (m, 3H) 4.95-5.04 (m, 1H)7.18 (d, J=8.73 Hz, 1H) 7.26 (s, 1H) 7.71 (dd, J=9.12, 2.38 Hz, 1H) 7.97(d, J=2.38 Hz, 1H); MS (DCI/NH₃) m/z 512 (M+H)⁺. Anal. calcdC₂₄H₃₁F₃N₂O₃S.0.5 H₂O: C, 57.68; H, 6.39; N, 8.18. Found: C, 57.79; H,6.39; N, 8.04.

Example 375N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-formyl-5-(trifluoromethyl)benzamideExample 375A 2-formyl-5-(trifluoromethyl)benzoic acid

To a 250 mL round-bottomed flask, was added 2.5 M n-butyllithium/hexane(8.92 mL, 22.30 mmol) in tetrahydrofuran (40 mL) and cooled to −78° C.,followed by dropwise addition of 2-bromo-5-(trifluoromethyl)benzoic acid(3 g, 11.15 mmol) in tetrahydrofuran (20 mL). After 30 minN,N-dimethylformamide (0.978 g, 13.38 mmol) was added and the solutionslowly allowed to warm to rt. To the reaction was added saturatedammonium chloride solution, followed by addition of saturated NaHCO₃solution until basic. The aqueous layer was separated, and 2 N HCl wasadded until acidic. The mixture was extracted with ethyl acetate (3×20mL). The organic layers were combined, dried, filtered, andconcentrated. The resulting solid was used without further purification.MS (DCI/NH₃) m/z 512 (M+NH₄)⁺.

Example 375B 2-formyl-5-(trifluoromethyl)benzoyl chloride

A solution of Example 375A (0.6 g) and thionyl chloride (3.27 g, 27.5mmol) was refluxed for 2 hr. The reaction solution was cooled to roomtemperature, concentrated, azeotroped with toluene, and used withoutfurther purification.

Example 375CN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-formyl-5-(trifluoromethyl)benzamide

The title compound was prepared and isolated as described in Example372B, substituting Example 375B for 2-fluoro-(5-trifluoromethyl)benzoylchloride in 25% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.34 (s, 9H)1.58-1.70 (m, 1H) 1.77-1.92 (m, 2H) 1.93-2.04 (m, 1H) 3.62-3.70 (m, 1H)3.76-3.84 (m, 1H) 4.22-4.32 (m, 3H) 7.39 (s, 1H) 7.81 (d, J=8.14 Hz, 1H)8.00-8.03 (m, 1H) 8.37-8.38 (m, 1H) 10.62 (s, 1H); MS (APCI) m/z 441(M+H)⁻.

Example 376N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-3-(trifluoromethyl)benzamide

The title compound was obtained as a side product from Example 375C. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 1.64-1.76 (m, 1H) 1.78-1.90(m, 2H) 1.91-2.04 (m, 1H) 3.62-3.72 (m, 1H) 3.76-3.85 (m, 1H) 4.26-4.39(m, 3H) 7.32 (s, 1H) 7.71-7.77 (m, 1H) 7.89-7.92 (m, 1H) 8.41-8.47 (m,2H); MS (DCI/NH₃) m/z 413 (M+H)⁺.

Example 3772-(azetidin-1-ylmethyl)-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

In a 20 mL vial, to a solution of Example 375C (52 mg, 0.118 mmol) indichloromethane (2 mL) was added azetidine (20.22 mg, 0.354 mmol),followed by addition of acetic acid (7.09 mg, 0.118 mmol) and sodiumtriacetoxyborohydride (37.5 mg, 0.177 mmol) and the mixture was stirredfor 2 hr. The reaction was quenched with saturated NaHCO₃ and extractedwith dichloromethane (3×5 mL). The organics were combined, dried,filtered, concentrated and the residue was purified by columnchromatography using an Analogix® Intelliflash280™ (SiO₂, gradientelution over 25 min with solvents A:B (100:0 to 10:90); solventA=CH₂Cl₂; solvent B=7M NH₃/MeOH (1):CH₂Cl₂ (9)) to afford the titlecompound in 79% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.34 (s, 9H)1.61-1.76 (m, 1H) 1.79-1.91 (m, 2H) 1.91-2.06 (m, 3H) 3.18 (t, J=6.94Hz, 4H) 3.60-3.71 (m, 1H) 3.74-3.85 (m, 1H) 4.06 (s, 2H) 4.23-4.36 (m,3H) 7.32 (s, 1H) 7.74-7.78 (m, 2H) 8.21-8.25 (m, 1H); MS (DCI/NH₃) m/z482 (M+H)⁺. Anal. calcd C₂₅H₃₂F₃N₃O₂S.0.3 C₆H₆: C, 62.02; H, 6.56; N,8.10. Found: C, 61.94; H, 6.43; N, 8.38.

Example 378N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)benzamide

The title compound was prepared and isolated as described in Example377, substituting pyrrolidine for azetidine in 72% yield. ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 1.62-1.72 (m, 5H) 1.79-1.88 (m, 2H)1.90-1.98 (m, 1H) 2.43-2.50 (m, 4H) 3.62-3.70 (m, 1H) 3.76-3.83 (m, 1H)4.10 (s, 2H) 4.22-4.33 (m, 3H) 7.30 (s, 1H) 7.76-7.86 (m, 2H) 8.16 (d,J=1.70 Hz, 1H); MS (DCI/NH₃) m/z 496 (M+H)⁺.

Example 379N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-5-(trifluoromethyl)benzamide

The title compound was prepared as described in Example 377,substituting (R)-pyrrolidin-3-ol for azetidine, and isolated bypreparative HPLC on a Phenomenex Luna Combi-HTS C8(2) column (5 μm, 100Å, 2.1 mm×30 mm), using a gradient of 10-100% acetonitrile (A) and 10 mMammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A.0.5 min post-run delay) in 70% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.33 (s, 9H) 1.53-1.69 (m, 2H) 1.78-1.89 (m, 2H) 1.92-2.04 (m, 2H) 2.35(dd, J=9.52, 3.57 Hz, 1H) 2.42-2.48 (m, 1H) 2.58-2.74 (m, 2H) 3.61-3.71(m, 1H) 3.75-3.84 (m, 1H) 4.09-4.11 (d, J=5.95 Hz, 2H) 4.16-4.27 (m, 3H)4.29-4.33 (m, 1H) 4.67 (d, J=4.36 Hz, 1H) 7.30 (s, 1H) 7.76-7.81 (m, 1H)7.83-7.88 (m, 1H) 8.17-8.18 (m, 1H); MS (DCI/NH₃) m/z 512 (M+H)⁺.

Example 380N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(3S)-3-hydroxypyrrolidin-1-yl]methyl}-5-(trifluoromethyl)benzamide

The title compound was prepared as described in Example 377,substituting (S)-pyrrolidin-3-ol for azetidine, and isolated bypreparative HPLC on a Phenomenex Luna Combi-HTS C8(2) column (5 μm, 100Å, 2.1 mm×30 mm), using a gradient of 10-100% acetonitrile (A) and 10 mMammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A.0.5 min post-run delay) in 60% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.33 (s, 9H) 1.53-1.60 (m, 1H) 1.62-1.69 (m, 1H) 1.77-1.89 (m, 2H)1.92-2.04 (m, 2H) 2.32-2.47 (m, 2H) 2.59-2.74 (m, 2H) 3.62-3.70 (m, 1H)3.75-3.84 (m, 1H) 4.02-4.13 (m, 2H) 4.17-4.33 (m, 4H) 4.67 (d, J=4.07Hz, 1H) 7.30 (s, 1H) 7.76-7.81 (m, 1H) 7.83-7.88 (m, 1H) 8.17 (s, 1H);MS (DCI/NH₃) m/z 512 (M+H)⁺.

Example 381N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methyl-5-(trifluoromethyl)benzamideExample 381A 2-methyl-5-(trifluoromethyl)benzoyl chloride

The title compound was prepared and isolated using the method describedin Example 375B, substituting 2-methyl-5-trifluoromethyl benzoic acidfor Example 375A.

Example 381BN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methyl-5-(trifluoromethyl)benzamide

The title compound was prepared and isolated as described in Example372B, substituting Example 381A for 2-fluoro-(5-trifluoro)benzoylchloride in 63% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H)1.60-1.72 (m, 1H) 1.78-1.86 (m, 2H) 1.87-1.99 (m, 1H) 2.67 (s, 3H)3.62-3.70 (m, 1H) 3.75-3.83 (m, 1H) 4.23-4.34 (m, 3H) 7.31 (s, 1H) 7.50(d, J=8.14 Hz, 1H) 7.70 (dd, J=7.97, 1.86 Hz, 1H) 8.28 (d, J=2.03 Hz,1H); MS (DCI/NH₃) m/z 427 (M+H)⁺.

Example 3822-(azetidin-3-yloxy)-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamideExample 382A tert-butyl3-[2-{[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]carbamoyl}-4-(trifluoromethyl)phenoxy]azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (4 g, 23.09mmol) in tetrahydrofuran (30 mL) was added sodium tert-butoxide (2.330g, 24.25 mmol). The mixture was stirred at room temperature for 20minutes before Example 372B (4.97 g, 11.55 mmol) was added. The mixturewas stirred at room temperature for 2 hr, quenched with saturatedaqueous ammonium chloride and extracted with ethyl acetate (3×30 mL).The organic layers were combined, washed with brine, dried, filtered,concentrated and the residue was purified by column chromatography usingan Analogix® Intelliflash280™ (SiO₂, 0-100% ethyl acetate in hexane over25 min) to afford the title compound (6.32 g, 10.83 mmol, 94% yield). ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 1.39 (s, 9H) 1.58-1.69 (m, 1H)1.76-1.87 (m, 2H) 1.88-1.99 (m, 1H) 3.60-3.70 (m, 1H) 3.75-3.86 (m, 3H)4.20-4.22 (m, 2H) 4.29-4.35 (m, 3H) 5.09-5.17 (m, 1H) 7.00 (d, J=8.48Hz, 1H) 7.73 (dd, J=8.82, 2.37 Hz, 1H) 8.04 (d, J=2.37 Hz, 1H); MS(DCI/NH₃) m/z 584 (M+H)⁺.

Example 382B2-(azetidin-3-yloxy)-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

To a solution of Example 382A (500 mg, 0.857 mmol) in ethyl acetate (1mL) was added sulfuric acid (84 mg, 0.857 mmol) in ethyl acetate (0.5mL). The mixture was stirred at room temperature for 6 hr. More sulfuricacid (84 mg, 0.857 mmol) was added and the reaction was heated at 75° C.overnight. The reaction mixture was cooled to room temperature andfiltered. The solid was washed with ethyl acetate. The title compoundwas obtained as a disulfate salt (175 mg, 30%). ¹H NMR (300 MHz, CD₃OD)δ ppm 1.44 (s, 9H) 1.64-1.76 (m, 1H) 1.83-2.00 (m, 2H) 2.08-2.19 (m, 1H)3.74-3.90 (m, 2H) 4.30-4.38 (m, 3H) 4.39-4.48 (m, 1H) 4.54-4.66 (m, 3H)5.34-5.41 (m, 1H) 7.06 (d, J=8.72 Hz, 1H) 7.47 (s, 1H) 7.84 (dd, J=9.12,2.38 Hz, 1H) 8.26 (d, J=2.38 Hz, 1H); (DCI/NH₃) m/z 484 (M+H)⁺. Anal.calcd C₂₃H₂₈F₃N₃O₃S.2 H₂SO₄: C, 40.64; H, 4.75; N, 6.18. Found: C,40.66; H, 4.57; N, 6.04.

Example 383N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(1-methylazetidin-3-yl)oxy]-5-(trifluoromethyl)benzamideExample 383A2-(azetidin-3-yloxy)-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

To a solution of Example 382A (0.619 g, 1.06 mmol) in dichloromethane (2mL) was added 2,2,2-trifluoroacetic acid (1 mL, 10.60 mmol). The mixturewas stirred at room temperature for 2 hr and then concentrated as theTFA salt.

Example 383BN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(1-methylazetidin-3-yl)oxy]-5-(trifluoromethyl)benzamide

To Example 383A (317 mg, 0.53 mmol) in dichloromethane (5 mL) was addeda solution of formaldehyde in water (318 μL, 30%, 95 mg), sodium acetate(130 mg, 1.590 mmol) and sodium triacetoxyborohydride (674 mg, 3.18mmol). The mixture was stirred at room temperature overnight andquenched with saturated aqueous NaHCO₃ and extracted withdichloromethane (3×10 mL). The combined organic layers were dried,filtered, concentrated under reduced pressure, and the residue waspurified by column chromatography using an Analogix® Intelliflash280™(SiO₂, gradient elution over 25 min with solvents A:B (100:0 to 10:90);solvent A=CH₂Cl₂; solvent B=7M NH₃/MeOH (1):CH₂Cl₂ (9)) to provide thetitle compound (105 mg, 0.211 mmol, 39.8% yield). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.33 (s, 9H) 1.67-1.70 (m, 1H) 1.76-1.85 (m, 2H)1.88-1.93 (m, 1H) 2.29 (s, 3H) 2.96-3.02 (m, 2H) 3.63-3.67 (m, 1H)3.73-3.83 (m, 3H) 4.21-4.23 (m, 2H) 4.31-4.33 (m, 1H) 4.87-4.89 (m, 1H)6.99-7.02 (m, 1H), 7.27 (s, 1H) 7.70-7.73 (m, 1H) 8.00-8.02 (m, 1H); MS(DCI/NH₃) m/z 498 (M+H)⁺.

Example 384N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(3R)-pyrrolidin-3-yloxy]-5-(trifluoromethyl)benzamideExample 384Atert-butyl(3R)-3-[2-{[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]carbamoyl}-4-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxylate

The title compound was prepared and isolated as described in Example373, substituting (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate for(R)-1-methylpyrrolidin-3-ol in 88% yield. ¹H NMR (300 MHz, DMSO-d₆) δppm 1.32 (s, 9H) 1.38 (s, 9H) 1.57-1.68 (m, 1H) 1.75-1.84 (m, 2H)1.86-1.95 (m, 1H) 2.10-2.16 (m, 2H) 3.34-3.45 (m, 3H) 3.53-3.68 (m, 2H)3.73-3.82 (m, 1H) 4.15-4.22 (m, 2H) 4.22-4.31 (m, 1H) 5.13-5.20 (m, 1H)7.27 (s, 1H) 7.30-7.34 (m, 1H) 7.75 (dd, J=8.92, 2.18 Hz, 1H) 7.97-7.99(m, 1H); MS (DCI/NH₃) m/z 598 (M+H)⁺.

Example 384BN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(3R)-pyrrolidin-3-yloxy]-5-(trifluoromethyl)benzamide

To a solution of Example 384A (1.223 g, 2.046 mmol) in dichloromethane(5 mL) was added 2,2,2-trifluoroacetic acid (2.333 g, 20.46 mmol). Themixture was stirred at room temperature for 2 hr and then concentrated.The mixture was taken up in dichloromethane and washed with sodiumbicarbonate. The organic layers were combined, dried and concentrated togive the title compound (0.92 g, 90%). ¹H NMR (300 MHz, CDCl₃) δ ppm1.37 (s, 9H) 1.58-1.72 (m, 1H) 1.79-1.94 (m, 2H) 2.01-2.15 (m, 3H)2.96-3.06 (m, 2H) 3.23-3.34 (m, 2H) 3.74-3.89 (m, 2H) 4.14-4.21 (m, 1H)4.24-4.32 (m, 1H) 4.39-4.46 (m, 1H) 4.97-5.03 (m, 1H) 6.88 (s, 1H) 7.05(d, J=8.73 Hz, 1H) 7.60 (dd, J=8.72, 2.38 Hz, 1H) 8.17 (d, J=2.38 Hz,1H); MS (DCI/NH₃) m/z 498 (M+H)⁺. Anal. calcd C₂₄H₃₀F₃N₃O₃S.1.2 H₂O: C,55.52; H, 6.29; N, 8.09. Found: C, 55.39; H, 6.63; N, 8.01.

Example 385N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(3S)-pyrrolidin-3-yloxy]-5-(trifluoromethyl)benzamideExample 385Atert-butyl(3S)-3-[2-{[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]carbamoyl}-4-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxylate

The title compound was prepared and isolated as described in Example373, substituting (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate for(R)-1-methylpyrrolidin-3-ol in 84% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm1.36 (s, 9H) 1.45 (s, 9H) 1.67-1.72 (m, 1H) 1.75-1.91 (m, 2H) 1.91-2.15(m, 2H) 2.23-2.29 (m, 1H) 3.46-3.61 (m, 3H) 3.65-3.69 (m, 1H) 3.73-3.88(m, 2H) 4.13-4.29 (m, 2H) 4.36-4.48 (m, 1H) 4.99-5.03 (m, 1H) 6.88 (s,1H) 6.97 (d, J=8.72 Hz, 1H) 7.57-7.61 (m, 1H) 8.18 (d, J=2.38 Hz, 1H);MS (DCI/NH₃) m/z 598 (M+H)⁺.

Example 385BN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(3S)-pyrrolidin-3-yloxy]-5-(trifluoromethyl)benzamide

The title compound was prepared and isolated as described in Example384B, substituting Example 385A for Example 384A in 61% yield. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.32 (s, 9H) 1.60-1.69 (m, 1H) 1.77-1.86 (m,2H) 1.87-1.98 (m, 2H) 2.03-2.15 (m, 1H) 2.95-3.11 (m, 3H) 3.20-3.26 (m,2H) 3.61-3.69 (m, 1H) 3.75-3.83 (m, 1H) 4.21-4.22 (m, 2H) 4.24-4.33 (m,1H) 5.11-5.14 (m, 1H) 7.28 (s, 1H) 7.31 (d, J=8.82 Hz, 1H) 7.76 (dd,J=8.82, 2.03 Hz, 1H) 8.03 (d, J=2.03 Hz, 1H); MS (DCI/NH₃) m/z 498(M+H)⁺. Anal. calcd C₂₄H₃₀F₃N₃O₃S.0.4 EtOAc.0.3 CH₂Cl₂: C, 53.18; H,5.79; N, 7.27. Found: C, 53.33; H, 5.47; N, 6.94.

Example 386 Xueqing WangN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)-2-vinylbenzamideExample 386A 2-bromo-5-(trifluoromethyl)benzoyl chloride

The title compound was prepared using the method described in Example375B, substituting 2-bromo-5-(trifluoromethyl)benzoic acid for Example375A.

Example 386B2-bromo-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

The title compound was prepared as described in Example 372B,substituting Example 386A for 2-fluoro-5-(trifluoromethyl)benzoylchloride in 88% yield. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H)1.54-1.69 (m, 1H) 1.77-1.86 (m, 2H) 1.88-1.97 (m, 1H) 3.61-3.69 (m, 1H)3.74-3.82 (m, 1H) 4.21-4.34 (m, 3H) 7.34 (s, 1H) 7.71 (dd, J=8.33, 2.38Hz, 1H) 7.93 (d, J=8.33 Hz, 1H) 8.08 (d, J=2.38 Hz, 1H); MS (DCI/NH₃)m/z 491 (M+H)⁺.

Example 386CN-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)-2-vinylbenzamide

To a solution Example 386B (200 mg, 0.407 mmol) and dibutylvinylboronate(150 mg, 0.814 mmol) in 1,2-dimethoxyethane (1 mL) and methyl alcohol(0.500 mL) was added palladium tetrakistriphenylphosphine (47.0 mg,0.041 mmol) and cesium fluoride (185 mg, 1.22 mmol). This mixture washeated in a microwave at 110° C. for 15 min. The reaction mixture wascooled to room temperature and concentrated, and the residue waspurified by column chromatography using an Analogix® Intelliflash280™(SiO₂, 0-30% ethyl acetate in hexane over 25 min) to obtain the titlecompound (150 mg, 84%). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.36 (s, 9H)1.61-1.73 (m, 1H) 1.79-1.95 (m, 2H) 2.02-2.13 (m, 1H) 3.75-3.89 (m, 2H)4.14-4.24 (m, 1H) 4.27-4.33 (m, 1H) 4.42-4.48 (m, 1H) 5.34-5.41 (m, 1H)5.64-5.72 (m, 1H) 6.88 (s, 1H) 7.60-7.73 (m, 3H) 8.39 (s, 1H); MS(DCI/NH₃) m/z 439 (M+H)⁺.

Example 387 tert-butyl4-[2-({[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-4-trifluoromethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate

The title compound was prepared and isolated as described in Example386C, substituting1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-ylboronic acid fordibutylvinylboronate in 93% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.36(s, 9H) 1.48 (s, 9H) 1.64-1.70 (m, 1H) 1.79-1.90 (m, 2H) 1.99-2.10 (m,1H) 2.42-2.46 (m, 1H) 3.59-3.63 (m, 2H) 3.70-3.88 (m, 3H) 4.03-4.07 (m,2H) 4.10-4.17 (m, 1H) 4.22-4.27 (m, 1H) 4.39-4.45 (m, 1H) 5.63-5.67 (m,1H) 6.88 (s, 1H) 7.31 (d, J=7.93 Hz, 1H) 7.60 (dd, J=7.73, 1.78 Hz, 1H)8.21-8.24 (m, 1H); MS (DCI/NH₃) m/z 594 (M+H)⁺.

Example 388N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)benzamide

The title compound was prepared and isolated using the method in Example384B, substituting Example 387 for example 384A in 61% yield. ¹H NMR(300 MHz, CDCl₃) δ ppm 1.36 (s, 9H) 1.64-1.68 (m, 1H) 1.81-1.91 (m, 2H)2.03-2.11 (m, 2H) 2.31-2.33 (m, 1H) 3.10 (t, J=5.55 Hz, 2H) 3.51-3.55(m, 2H) 3.75-3.90 (m, 2H) 4.10-4.21 (m, 1H) 4.25-4.32 (m, 1H) 4.46 (dd,J=13.68, 2.97 Hz, 1H) 5.68-5.72 (m, 1H) 6.88 (s, 1H) 7.32 (d, J=7.93 Hz,1H) 7.60 (dd, J=8.13, 1.78 Hz, 1H) 8.20 (d, J=1.59 Hz, 1H); MS (DCI/NH₃)m/z 494 (M+H)⁺.

Example 389N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-ethyl-5-(trifluoromethylbenzamide

A mixture of Example 386C (120 mg, 0.274 mmol) and palladium hydroxide(19.22 mg, 0.137 mmol) in methyl alcohol (2.0 mL) was hydrogenated under1 atm H₂ at 20° C. for 4 hr. The reaction was filtered and the filtrateconcentrated. The residue was isolated by preparative HPLC on aPhenomenex Luna Combi-HTS C8(2) column (5 μm, 100 Å, 2.1 mm×30 mm),using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetatein water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A 0.5 min post-rundelay) to provide the title compound (92 mg, 76%). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.19 (t, J=7.29 Hz, 3H) 1.33 (s, 9H) 1.59-1.70 (m, 1H)1.78-1.87 (m, 2H) 1.88-1.99 (m, 1H) 3.09 (q, J=7.46 Hz, 2H) 3.62-3.70(m, 1H) 3.75-3.83 (m, 1H) 4.22-4.32 (m, 3H) 7.30 (s, 1H) 7.52 (d, J=8.14Hz, 1H) 7.72 (d, J=7.12 Hz, 1H) 8.19 (s, 1H); MS (DCI/NH₃) m/z 441(M+H)⁺. Anal. calcd C₂₂H₂₇F₃N₂O₂S.0.3 H₂O: C, 59.26; H, 6.24; N, 6.28.Found: C, 59.14; H, 6.06; N, 6.20.

Example 390N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(E)-2-(methylsulfonyl)vinyl]-5-(trifluoromethyl)benzamide

To a solution of Example 386B (172 mg, 0.350 mmol), triethylamine (53mg, 0.525 mmol) and methylvinylsulfone (55.7 mg, 0.525 mmol) inacetonitrile (1 mL) was added palladium acetate (4.72 mg, 0.021 mmol)and tri(o-tolyl)phosphine (23.44 mg, 0.077 mmol). This mixture washeated in a microwave at 140° C. for 30 min. The reaction was heatedanother 30 min at 180° C. The reaction mixture was cooled to roomtemperature and filtered. The residue was purified by preparative HPLCon a Phenomenex Luna Combi-HTS C8(2) column (5 μm, 100 Å, 2.1 mm×30 mm),using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetatein water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-rundelay) to provide the title compound (85 mg, 47%). ¹H NMR (300 MHz,CDCl₃) δ ppm 1.38 (s, 9H) 1.62-1.71 (m, 1H) 1.76-1.92 (m, 2H) 2.02-2.14(m, 1H) 3.08 (s, 3H) 3.73-3.87 (m, 2H) 4.22-4.34 (m, 2H) 4.50 (d,J=11.10 Hz, 1H) 6.80 (d, J=15.47 Hz, 1H) 6.97 (s, 1H) 7.59-7.72 (m, 2H)8.52 (s, 1H) 8.83 (d, J=15.47 Hz, 1H); MS (DCI/NH₃) m/z 517 (M+H)⁺.

Example 391N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(methylsulfonyl)ethyl]-5-(trifluoromethyl)benzamide

The title compound was prepared and isolated using the method describedin Example 389, substituting Example 390 for Example 386C in 87% yield.¹H NMR (300 MHz, CDCl₃) δ ppm 1.38 (m, 9H) 1.64-1.74 (m, 1H) 1.81-1.97(m, 2H) 2.04-2.15 (m, 1H) 3.01 (s, 3H) 3.40-3.47 (m, 2H) 3.59-3.67 (m,2H) 3.75-3.90 (m, 2H) 4.18-4.26 (m, 1H) 4.27-4.34 (m, 1H) 4.46 (dd,J=13.39, 2.88 Hz, 1H) 6.91 (s, 1H) 7.43 (d, J=8.14 Hz, 1H) 7.60-7.66 (m,1H) 8.51 (d, J=1.70 Hz, 1H); MS (DCI/NH₃) m/z 519 (M+H)⁺.

Example 392N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-5-(trifluoromethyl)benzamide

In a vial (5 mL), a mixture of Example 375C (88 mg, 0.200 mmol),support-bound cyanoborohydride resin (0.256 g, 0.599 mmol),(S)-pyrrolidin-2-ylmethanol (60 mg, 0.593 mmol), and acetic acid (18 mg,0.300 mmol) in dichloromethane (1 mL) and methyl alcohol (1 mL) wasshaken on an orbit shaker for 2 hr. The reaction was filtered,concentrated and the residue was purified by preparative HPLC on aPhenomenex Luna Combi-HTS C8(2) column (5 μm, 100 Å, 2.1 mm×30 mm),using a gradient of 10-100% acetonitrile (A) and 0.1% trifluoroaceticacid in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A,0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5min post-run delay) in 38% yield as TFA salt. ¹H NMR (300 MHz, CD₃OD) δppm 1.41 (s, 9H) 1.72-1.81 (m, 1H) 1.88-1.99 (m, 2H) 2.05-2.20 (m, 3H)2.27-2.41 (m, 1H) 3.34-3.42 (m, 1H) 3.52-3.66 (m, 1H) 3.67-3.82 (m, 4H)3.85-3.96 (m, 1H) 4.36-4.46 (m, 3H) 4.57 (d, J=12.69 Hz, 1H) 4.86-4.93(m, 2H) 7.28 (s, 1H) 7.76-7.82 (m, 1H) 7.87-7.94 (m, 1H) 8.73-8.75 (m,1H); MS (DCI/NH₃) m/z 526 (M+H)⁺. Anal. calcd calcd C₂₆H₃₄F₃N₃O₃S.1.9CF₃CO₂H: C, 48.22; H, 4.87; N, 5.66. Found: C, 48.28; H, 4.63; N, 5.67.

Example 393N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(morpholin-4-ylmethyl)-5-(trifluoromethyl)benzamide

The title compound was prepared and purified as described in Example392, substituting morpholine for (S)-pyrrolidin-2-ylmethanol in 42%yield as the TFA salt. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.41 (s, 9H)1.71-1.82 (m, 1H) 1.88-1.98 (m, 2H) 2.06-2.13 (m, 1H) 3.36-3.40 (m, 2H)3.46-3.57 (m, 2H) 3.75-3.91 (m, 4H) 4.05-4.16 (m, 2H) 4.37-4.47 (m, 3H)4.68 (s, 2H) 7.29 (s, 1H) 7.76 (d, J=7.93 Hz, 1H) 7.92 (dd, J=7.93, 1.98Hz, 1H) 8.79 (s, 1H); MS (DCI/NH₃) m/z 512 (M+H)⁺. Anal. CalcdC₂₅H₃₂F₃N₃O₃S.1.9 CF₃CO₂H: C, 47.50; H, 4.69; N, 5.67. Found: C, 47.62;H, 4.67; N, 5.86.

Example 394N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(thiomorpholin-4-ylmethyl)-5-(trifluoromethyl)benzamide

The TFA salt of the title compound was prepared and purified asdescribed in Example 392, substituting thiomorpholine for(S)-pyrrolidin-2-ylmethanol in 45% yield. ¹H NMR (300 MHz, CD₃OD) δ ppm1.40 (s, 9H) 1.70-1.81 (m, 1H) 1.88-1.98 (m, 2H) 2.15-2.15 (m, 1H)2.93-3.02 (m, 2H) 3.04-3.14 (m, 2H) 3.40-3.48 (m, 2H) 3.73-3.93 (m, 4H)4.37-4.47 (m, 3H) 4.66 (s, 2H) 7.29 (s, 1H) 7.74-7.76 (m, 1H) 7.90-7.92(m, 1H) 8.75-8.77 (m, 1H); MS (DCI/NH₃) m/z 528 (M+H)⁺. Anal. calcdC₂₅H₃₂F₃N₃O₂S₂.1.1 CF₃CO₂H: C, 50.02; H, 5.11; N, 6.43. Found: C, 49.97;H, 5.05; N, 6.40.

Example 395N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzamide

The TFA salt of the title compound was prepared and purified asdescribed in Example 392, substituting N-methyl piperidine for(S)-pyrrolidin-2-ylmethanol in 45% yield. ¹H NMR (300 MHz, CD₃OD) δ ppm1.40 (s, 9H) 1.66-1.78 (m, 1H) 1.87-1.97 (m, 2H) 2.02-2.14 (m, 1H) 2.81(s, 3H) 2.94-3.08 (m, 4H) 3.18-3.28 (m, 4H) 3.72-3.81 (m, 1H) 3.85-3.93(m, 1H) 4.28-4.41 (m, 5H) 7.23 (s, 1H) 7.71-7.80 (m, 2H) 8.33 (s, 1H);MS (DCI/NH₃) m/z 525 (M+H)⁺. Anal. calcd C₂₆H₃₅F₃N₄O₂S.2.0 CF₃CO₂H: C,47.87; H, 4.95; N, 7.44. Found: C, 47.69; H, 4.92; N, 7.38.

Example 396N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(cyanomethyl)(methyl)amino]methyl}-5-(trifluoromethyl)benzamide

The title compound was prepared and purified as described in Example392, substituting 2-(methylamino)acetonitrile for(S)-pyrrolidin-2-ylmethanol in 45% yield. ¹H NMR (300 MHz, CD₃OD) δ ppm1.40 (s, 9H) 1.69-1.75 (m, 1H) 1.85-1.97 (m, 2H) 2.04-2.17 (m, 1H) 2.53(s, 3H) 3.73-3.80 (m, 1H) 3.85-3.92 (m, 3H) 4.29 (s, 2H), 4.30-4.42 (m,3H) 7.21 (s, 1H) 7.71-7.80 (m, 2H) 8.28-8.30 (m, 1H); MS (DCI/NH₃) m/z495 (M+H)⁺.

Example 397N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-5-(trifluoromethyl)benzamide

The TFA salt of the title compound was prepared and purified asdescribed in Example 392, substituting (R)-pyrrolidin-2-ylmethanol for(S)-pyrrolidin-2-ylmethanol in 60% yield. ¹H NMR (300 MHz, CD₃OD) δ ppm1.41 (s, 9H) 1.70-1.82 (m, 1H) 1.88-1.98 (m, 2H) 2.05-2.22 (m, 4H)2.33-2.37 (m, 1H) 3.33-3.40 (m, 1H) 3.51-3.59 (m, 1H) 3.68-3.82 (m, 4H)3.86-3.94 (m, 1H) 4.36-4.44 (m, 3H) 4.53-4.61 (m, 1H) 4.88-4.92 (m, 1H)7.28 (s, 1H) 7.75-7.81 (m, 1H) 7.90 (dd, J=7.97, 1.53 Hz, 1H) 8.74 (d,J=1.70 Hz, 1H); MS (DCI/NH₃) m/z 526 (M+H)⁺. Anal. calcdC₂₆H₃₄F₃N₃O₃S.2.0 CF₃CO₂H: C, 47.81; H, 4.81; N, 5.58. Found: C, 47.72;H, 4.91; N, 5.49.

Example 3982-[(tert-butylamino)methyl]-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide

The TFA salt of the title compound was prepared and purified asdescribed in Example 392, substituting tert-butyl amine for(S)-pyrrolidin-2-ylmethanol in 80% yield. ¹H NMR (300 MHz, CD₃OD) δ ppm1.40 (s, 9H) 1.55 (s, 9H) 1.71-1.82 (m, 1H) 1.88-1.98 (m, 2H) 2.04-2.15(m, 1H) 3.73-3.81 (m, 1H) 3.86-3.94 (m, 1H) 4.36-4.46 (m, 3H), 4.48 (s,2H) 7.27 (s, 1H) 7.76 (d, J=8.14 Hz, 1H) 7.88 (dd, J=7.97, 1.86 Hz, 1H)8.69 (d, J=1.36 Hz, 1H); MS (DCI/NH₃) m/z 498 (M+H)⁺. Anal. calcdC₂₅H₃₄F₃N₃O₂S.1.0 CF₃CO₂H: C, 53.02; H, 5.77; N, 6.87. Found: C, 52.92;H, 5.71; N, 6.80.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

What is claimed is:
 1. A compound according to formula (I),

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein R₁ is A, or A-alkylene-; R₂ is hydrogen,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkyl-S(O)₂—, aryl, arylalkyl, arylalkenyl, azidoalkyl, cyano,cycloalkyl, halo, haloalkyl, heteroaryl, heterocycle, —(CR₂₁R₂₂)_(m)—OH,R_(a)R_(b)N—, R_(a)R_(b)N-alkyl-, R_(c)R_(d)NC(O)—, or R₈—R₇—; R₃ isalkoxy, alkoxyalkyl, n-propyl, tert-butyl, alkylcarbonyl, alkyl-S(O)₂—,cyano, cycloalkyl, halo, haloalkyl, —(CR₃₁R₃₂)_(m)—OH, R_(a)R_(b)N—,R_(a)R_(b)N-alkyl-, or R₈—R₇—; or R₂ and R₃, together with the carbonatoms to which they are attached, form a 4-, 5-, 6-, or 7-memberedmonocyclic ring, optionally fused to benzo or oxadiazole, saidmonocyclic ring contains zero or one additional double bond, zero or oneoxygen atom, and zero or one nitrogen atom as ring atoms; twonon-adjacent atoms of said monocyclic ring are optionally linked by analkenylene bridge of 2, 3, or 4 carbon atoms, or optionally linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms, said monocyclic ring isindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents independently selected from the group consisting of oxo,alkyl, halo, —OH, —O(alkyl), and haloalkyl; two substituents on the samecarbon atom of said monocyclic ring, together with the carbon atom towhich they are attached, optionally form a 3-, 4-, 5-, or 6-memberedmonocyclic cycloalkyl ring, wherein the monocyclic cycloalkyl ring isoptionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from the group consisting of alkyl and haloalkyl;with the proviso that when R₂ and R₃, together with the carbon atom towhich they are attached, form a ring as represented by formula (viii),(ix), or (xi),

then R₁ is A or A-alkylene-; and with a further proviso that when R₂ andR₃ are other than forming a ring with the carbon atoms to which they areattached, then R₁ is alkoxyalkoxyalkyl, A or A-alkylene-; R₄ is alkyl,alkynyl, cycloalkyl, cycloalkenyl, or aryl; wherein the alkyl group isoptionally substituted with one substituent selected from the groupconsisting of alkoxy, alkoxycarbonyl, carboxy, halo, —OH, andR_(e)R_(f)N—; R₇ and R₈ are each independently aryl, cycloalkyl,cycloalkenyl, heteroaryl, or heterocycle; R_(a) and R_(b), at eachoccurrence, are each independently hydrogen, alkoxycarbonyl, alkyl,alkylcarbonyl, alkyl-S(O)₂—, or arylalkyl; R_(c) and R_(d), are eachindependently hydrogen or alkyl; R_(e) and R_(f), are each independentlyhydrogen, alkyl, or alkylcarbonyl; A is a 4-, 5-, 6-, 7-, 8-, or9-membered monocyclic heterocycle containing zero or one double bond,one or two oxygen, and zero or one nitrogen as ring atoms; twonon-adjacent atoms of said heterocycle ring can be optionally linked byan alkenylene bridge of 2, 3, or 4 carbon atoms, or optionally linked byan alkylene bridge of 1, 2, 3, or 4 carbon atoms; or A is furanyl,oxazolyl, isoxazolyl, or oxadiazolyl; each ring A is optionally fusedwith a monocyclic ring selected from the group consisting of benzo,cycloalkyl, cycloalkenyl, heterocycle and heteroaryl; and each A isindependently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from the group consisting of oxo,alkyl, halo, —OH, —O(alkyl), and haloalkyl; L₁ is a single bond or—NR_(g)—; R_(g) is hydrogen or alkyl; the aryl, cycloalkyl,cycloalkenyl, heterocycle, or heteroaryl moieties, as a substituent, oras part of a substituent, as represented by R₂, R₃, R₄, R_(a), R_(b),R₇, and R₈, are each independently unsubstituted or substituted with 1,2, 3, 4, 5, or 6 substituents independently selected from the groupconsisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfinyl,alkylsulfinylalkyl, alkyl-S(O)₂—, alkyl-S(O)₂—(CR₄₁R₄₂)_(p)═C(R₄₁)—,alkyl-S(O)₂—(CR₄₁R₄₂)_(p)—, alkyl-S—, alkyl-S—(CR₄₁R₄₂)_(p)—, alkynyl,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen,haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, oxo, —SH, N(O)₂,—C(R₄₁)═N—O(R₄₂), —(CR₄₁R₄₂)_(p)—C(R₄₁)═N—O(R₄₂), ═N—O(alkyl), ═N—OH,NZ₁Z₂—(CR₄₁R₄₂)_(p)—O—, —O—(CR₄₁R₄₂)_(p)-G₁, G₁, —NZ₁Z₂,—(CR₄₁R₄₂)_(p)—NZ₁Z₂, and (NZ₃Z₄)carbonyl; G₁ is a 4-, 5-, 6-, or7-membered monocyclic heterocycle containing one nitrogen atom andoptionally 1 or 2 additional heteroatom in the ring, wherein said ringis attached to the parent moiety through the nitrogen atom, and saidring is optionally substituted with 1, 2, 3, 4, or 5 substituentsselected from the group consisting of alkyl, alkenyl, alkynyl, halo,haloalkyl, ═N—CN, ═N—OR₅₁, —CN, oxo, —OR₅₁, —OC(O)R₅₁, —OC(O)N(R₅₁)₂,—S(O)₂R₅₂, —S(O)₂N(R₅₁)₂, —C(O)R₅₁, —C(O)OR₅₁, —C(O)N(R₅₁)₂, —N(R₅₁)₂,—N(R₅₁)C(O)R₅₁, —N(R₅₁)S(O)₂R₅₂, —N(R₅₁)C(O)O(R₅₂), —N(R₅₁)C(O)N(R₅₁)₂,—(CR_(1c)R_(1d))_(q)—OR₅₁, —(CR_(1c)R_(1d))_(q)—OC(O)R₅₁,—(CR_(1c)R_(1d))_(q)—OC(O)N(R₅₁)₂, —(CR_(1c)R_(1d))_(q)—S(O)₂R₅₂,—(CR_(1c)R_(1d))_(q)—S(O)₂N(R₅₁)₂, —(CR_(1c)R_(1d))_(q)—C(O)R₅₁,—(CR_(1c)R_(1d))_(q)—C(O)OR₅₁, —(CR_(1c)R_(1d))_(q)—C(O)N(R₅₁)₂,—(CR_(1c)R_(1d))_(q)—N(R₅₁)₂, —(CR_(1c)R_(1d))_(q)—N(R₅₁)C(O)R₅₁,—(CR_(1c)R_(1d))_(q)—N(R₅₁)S(O)₂R₅₂,—(CR_(1c)R_(1d))_(q)—N(R₅₁)C(O)O(R₅₂),—(CR_(1c)R_(1d))_(q)—N(R₅₁)C(O)N(R₅₁)₂, and —(CR_(1c)R_(1d))_(q)—CN;R₅₁, at each occurrence, is independently hydrogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, —(CR_(2c)R_(2d))_(u)—OR⁵³, monocyclic cycloalkyl, or—(CR_(2c)R_(2d))_(u)-(monocyclic cycloalkyl); wherein R₅₃ is hydrogen,C₁-C₄ alkyl, C₁-C₄ haloalkyl, monocyclic cycloalkyl, or—(CR_(2c)R_(2d))_(u)-(monocyclic cycloalkyl); R₅₂, at each occurrence,is independently C₁-C₄ alkyl, C₁-C₄ haloalkyl, monocyclic cycloalkyl, or—(CR_(2c)R_(2d))_(u)-(monocyclic cycloalkyl); the monocyclic cycloalkylmoiety, as a substituent, or as part of a substituent, as represented byR₅₁, R₅₂, and R₅₃ are each independently unsubstituted or substitutedwith 1, 2, 3, or 4 substituents selected from the group consisting ofC₁-C₄ alkyl, halo, hydroxy, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl; R₂₁, R₂₂, R₃₁, R₃₂, R₄₁, R₄₂, R_(1c), R_(1d), R_(2c), andR_(2d), at each occurrence, are each independently hydrogen, alkyl,haloalkyl, or halo; m, p, q, and u, at each occurrence, are eachindependently 1, 2, 3, or 4; Z₁ and Z₂ are each independently hydrogen,alkyl, alkoxyalkyl, alkylcarbonyl, cyanoalkyl, haloalkyl, or formyl; andZ₃ and Z₄ are each independently hydrogen, alkyl, haloalkyl, phenyl orbenzyl; wherein the phenyl moiety is optionally substituted with 1, 2,3, or 4 substituents selected from the group consisting of alkyl,hydroxyl, and haloalkyl.
 2. The compound of claim 1, or apharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein A is a 4-, 5-, 6-, 7-, 8-, or 9-memberedmonocyclic heterocycle containing zero or one double bond, one or twooxygen, and zero or one nitrogen as ring atoms; two non-adjacent atomsof said heterocycle ring can be optionally linked by an alkenylenebridge of 2, 3, or 4 carbon atoms, or optionally linked by an alkylenebridge of 1, 2, 3, or 4 carbon atoms; each ring A is optionally fusedwith a monocyclic ring selected from the group consisting of benzo,cycloalkyl, cycloalkenyl, heterocycle, and heteroaryl; and each A isindependently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from the group consisting of oxo,alkyl, halo, —OH, —O(alkyl), and haloalkyl.
 3. The compound of claim 2,or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein R₂ is hydrogen, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, aryl, halo, haloalkyl, or —(CR₂₁R₂₂)_(m)—OH;R₃ is n-propyl, tert-butyl, alkylcarbonyl, cycloalkyl, halo, haloalkyl,or —(CR₃₁R₃₂)_(m)—OH; L₁ is a bond; and R₄ is aryl, cycloalkyl, alkynyl,or alkyl; wherein the alkyl is optionally substituted with onesubstituent selected from the group consisting of alkoxycarbonyl, —OH,and R_(e)R_(f)N—.
 4. The compound of claim 3, or a pharmaceuticallyacceptable salt, prodrug, salt of a prodrug, or a combination thereof,wherein R₄ is optionally substituted phenyl.
 5. The compound of claim 2,or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein R₂ is hydrogen or alkyl; R₃ is n-propyl,tert-butyl, or —(CR₃₁R₃₂)_(m)—OH; L₁ is a bond; R₄ is optionallysubstituted phenyl.
 6. The compound of claim 2, or a pharmaceuticallyacceptable salt, prodrug, salt of a prodrug, or a combination thereof,wherein R₂ is hydrogen, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,aryl, halo, haloalkyl, or —(CR₂₁R₂₂)_(m)—OH; R₃ is n-propyl, tert-butyl,alkylcarbonyl, cycloalkyl, halo, haloalkyl, or —(CR₃₁R₃₂)_(m)—OH; L₁ isa NR_(g); and R₄ is cyclolalkyl, or alkyl; wherein the alkyl isoptionally substituted with one substituent selected from the groupconsisting of alkoxycarbonyl, —OH, and R_(e)R_(f)N—.
 7. The compound ofclaim 1, or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein R₁ is A-alkylene- and A isfuranyl, oxazolyl, isoxazolyl, or oxadiazolyl, each of which isoptionally substituted.
 8. The compound of claim 7, or apharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein R₂ is hydrogen, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, aryl, halo, haloalkyl, or —(CR₂₁R₂₂)_(m)—OH;R₃ is n-propyl, tert-butyl, alkylcarbonyl, cycloalkyl, halo, haloalkyl,or —(CR₃₁R₃₂)_(m)—OH; L₁ is a bond; and R₄ is aryl, cycloalkyl, alkynyl,or alkyl; wherein the alkyl is optionally substituted with onesubstituent selected from the group consisting of alkoxycarbonyl, —OH,and R_(e)R_(f)N—.
 9. The compound of claim 7, or a pharmaceuticallyacceptable salt, prodrug, salt of a prodrug, or a combination thereof,wherein R₂ is hydrogen or alkyl; R₃ is n-propyl, tert-butyl, or—(CR₃₁R₃₂)_(m)—OH; L₁ is a bond; R₄ is optionally substituted phenyl.10. The compound of claim 7, or a pharmaceutically acceptable salt,prodrug, salt of a prodrug, or a combination thereof, wherein R₂ ishydrogen, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, aryl, halo,haloalkyl, or —(CR₂₁R₂₂)_(m)—OH; R₃ is n-propyl, tert-butyl,alkylcarbonyl, cycloalkyl, halo, haloalkyl, or —(CR₃₁R₃₂)_(m)—OH; L₁ isa NR_(g); and R₄ is cyclolalkyl, or alkyl; wherein the alkyl isoptionally substituted with one substituent selected from the groupconsisting of alkoxycarbonyl, —OH, and R_(e)R_(f)N—.
 11. The compound ofclaim 1, or a pharmaceutically acceptable salt, prodrug, salt of aprodrug, or a combination thereof, wherein R₂ and R₃, together with thecarbon atoms to which they are attached, form a 4-, 5-, 6-, or7-membered monocyclic ring optionally fused to benzo or oxadiazole, saidmonocyclic ring contains zero or one additional double bond, zero oxygenatom and zero nitrogen atom as ring atoms; two non-adjacent atoms ofsaid monocyclic ring are linked by an alkenylene bridge of 2, 3, or 4carbon atoms, or linked by an alkylene bridge of 1, 2, 3, or 4 carbonatoms, said monocyclic ring is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom the group consisting of oxo, alkyl, halo, —OH, —O(alkyl), andhaloalkyl; two substituents on the same carbon atom of said monocyclicring, together with the carbon atom to which they are attached,optionally form a 3-, 4-, 5-, or 6-membered monocyclic cycloalkyl ring,wherein the monocyclic cycloalkyl ring is optionally substituted with 1,2, 3, 4, 5, or 6 substituents independently selected from the groupconsisting of alkyl and haloalkyl.
 12. The compound of claim 11, or apharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein R₄ is aryl, cycloalkyl, alkynyl, or alkyl;wherein the alkyl is optionally substituted with one substituentselected from the group consisting of alkoxycarbonyl, —OH, andR_(e)R_(f)N—.
 13. The compound of claim 1, or a pharmaceuticallyacceptable salt, prodrug, salt of a prodrug, or a combination thereof,wherein R₂ and R₃, together with the carbon atoms to which they areattached, form an optionally substituted ring as represented by


14. The compound of claim 1, or a pharmaceutically acceptable salt,prodrug, salt of a prodrug, or a combination thereof, wherein R₂ and R₃,together with the carbon atoms to which they are attached, form a 4-,5-, 6-, or 7-membered monocyclic ring optionally fused to benzo oroxadiazole, said monocyclic ring contains zero or one additional doublebond, and one oxygen atom and zero or one nitrogen atom as ring atoms;two non-adjacent atoms of said monocyclic ring can be optionally linkedby an alkenylene bridge of 2, 3, or 4 carbon atoms, or optionally linkedby an alkylene bridge of 1, 2, 3, or 4 carbon atoms, said monocyclicring is independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents independently selected from the group consisting of oxo,alkyl, halo, —OH, —O(alkyl), and haloalkyl; two substituents on the samecarbon atom of said monocyclic ring, together with the carbon atom towhich they are attached, optionally form a 3-, 4-, 5-, or 6-memberedmonocyclic cycloalkyl ring, wherein the monocyclic cycloalkyl ring isoptionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from the group consisting of alkyl and haloalkyl.15. The compound of claim 14, or a pharmaceutically acceptable salt,prodrug, salt of a prodrug, or a combination thereof, wherein R₄ isaryl, cycloalkyl, alkynyl, or alkyl; wherein the alkyl is optionallysubstituted with one substituent selected from the group consisting ofalkoxycarbonyl, —OH, and R_(e)R_(f)N—.
 16. The compound of claim 1, or apharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein R₂ and R₃, together with the carbon atomsto which they are attached, form a ring as represented by


17. The compound of claim 1 selected from the group consisting of5-chloro-2-methoxy-N-[(2Z)-5-propyl-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]benzamide;5-chloro-N-[(2Z)-5-chloro-3-(tetrahydrofuran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;5-bromo-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;N-[(2Z)-5-acetyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-(1,3-dioxolan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-N-[(2Z)-5-chloro-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;5-chloro-N-[(2Z)-5-chloro-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-2-methoxy-N-[(2Z)-3-(tetrahydro-2H-pyran-4-ylmethyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-2(3H)-ylidene]benzamide;N-[(2Z)-5-acetyl-4-methyl-3-(oxetan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-N-[(2Z)-4,4-dimethyl-1-(oxetan-2-ylmethyl)-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene]-2-methoxybenzamide;5-chloro-N-{(2Z)-4,4-dimethyl-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene}-2-methoxybenzamide;N-[(2Z)-5-acetyl-4-methyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-acetyl-4-methyl-3-(tetrahydro-2H-pyran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;5-chloro-2-methoxy-N-[(2Z)-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3-thiazol-2(3H)-ylidene]benzamide;5-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-(tetrahydro-2H-pyran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;5-chloro-N-[(2Z)-3-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;5-chloro-N-[(2Z)-6,6-dimethyl-4-oxo-3-[(2R)-tetrahydrofuran-2-ylmethyl]-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]-2-methoxybenzamide;5-chloro-N-[(2Z)-3-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;N-[(2Z)-5-acetyl-3-(1,4-dioxan-2-ylmethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-(oxetan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;5-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-(tetrahydrofuran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;5-chloro-N-[(2Z)-3-(1,4-dioxan-2-ylmethyl)-5-(1-hydroxy-1-methylethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-3-methoxy-2-naphthamide;N-[(2Z)-5-tert-butyl-3-[(3-methyloxetan-3-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-2-methoxy-N-[(2Z)-3-(tetrahydrofuran-2-ylmethyl)-3,4,5,6-tetrahydro-2H-cyclopenta[d][1,3]thiazol-2-ylidene]benzamide;5-chloro-2-methoxy-N-[(2Z)-3-(tetrahydro-2H-pyran-4-ylmethyl)-3,4,5,6-tetrahydro-2H-cyclopenta[d][1,3]thiazol-2-ylidene]benzamide;N-[(2Z)-5-tert-butyl-3-(oxetan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-(tetrahydro-2H-pyran-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-(1,4-dioxan-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-(tetrahydrofuran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-(tetrahydro-2H-pyran-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[(2S)-5-oxotetrahydrofuran-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-acetyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(2,2,2-trifluoroethoxy)benzamide;N-[(2Z)-5-tert-butyl-3-[(5-methyltetrahydrofuran-2-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(5,5-dimethyltetrahydrofuran-2-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(2-methoxyethoxy)benzamide;5-chloro-2-methoxy-N-[(2Z)-5-(1-methylcyclopropyl)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]benzamide;5-chloro-N-[(2Z)-5-(1-hydroxy-3-iodo-1-methylpropyl)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-isopropoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-ethoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-[(2-methoxyethyl)(methyl)amino]benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(difluoromethoxy)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(trifluoromethoxy)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-(2,2,2-trifluoroethoxy)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-[3-(dimethylamino)propoxy]benzamide;N-[(2Z)-5-tert-butyl-3-[(2S)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-2-methoxy-N-[(2Z)-4,4,6,6-tetramethyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-4,6-dihydrofuro[3,4-d][1,3]thiazol-2(3H)-ylidene]benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-cyano-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-2-methoxy-N-{(2Z)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4,5,6,7,8-hexahydro-2H-4,7-epoxycyclohepta[d][1,3]thiazol-2-ylidene}benzamide;5-chloro-2-methoxy-N-[(2Z)-3-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydro-4H-pyrano[3,4-d][1,3]thiazol-2(3H)-ylidene]benzamide;5-chloro-2-methoxy-N-{(2Z)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,4,6,7-tetrahydro-2H-pyrano[4,3-d][1,3]thiazol-2-ylidene}benzamide;N-[(2Z)-5-tert-butyl-3-(2-morpholin-4-ylethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-hydroxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methoxy-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-tetrahydro-2H-pyran-4-yl-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{2-[cis-2,6-dimethylmorpholin-4-yl]ethyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;5-chloro-N-[(2Z)-5-(1-hydroxy-1-methylethyl)-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(2,2,2-trifluoroethoxy)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-[(E)-(hydroxyimino)methyl]benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-formylbenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-N′-(1,1-dimethylpropyl)urea;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-N′-(2-hydroxy-1,1-dimethylethyl)urea;methylN-({[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-2-methylalaninate;N-[(2Z)-5-tert-butyl-3-(1,3-oxazol-2-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-(1,2,4-oxadiazol-3-ylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-(2-furylmethyl)-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-ethoxy-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-{[(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl}-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-4-methyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-fluoro-3-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(dimethylamino)ethoxy]-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(dimethylamino)-2-methylpropoxy]-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(2-morpholin-4-ylethoxy)-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(diethylamino)ethoxy]-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(1,1-dioxidothiomorpholin-4-yl)ethoxy]-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(2-piperidin-1-ylethoxy)-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(3-methoxy-3-methylbutoxy)-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(2-oxopyrrolidin-1-yl)ethoxy]-5-(trifluoromethyl)benzamide;methyl2-({[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-4-(trifluoromethyl)benzoate;2-[2-(tert-butylamino)ethoxy]-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(5-methylisoxazol-3-yl)methyl]-1,3-thiazol-2(3H)-ylidene]-5-chloro-2-methoxybenzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-cyano-5-(trifluoromethyl)benzamide;2-tert-butoxy-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-formyl-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-3-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-methyl-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)-2-vinylbenzamide;tert-butyl4-[2-({[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-4-(trifluoromethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-(1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-ethyl-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[(E)-2-(methylsulfonyl)vinyl]-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-[2-(methylsulfonyl)ethyl]-5-(trifluoromethyl)benzamide;N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-2-{[(cyanomethyl)(methyl)amino]methyl}-5-(trifluoromethyl)benzamide;and2-[(tert-butylamino)methyl]-N-[(2Z)-5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-ylidene]-5-(trifluoromethyl)benzamide;or a pharmaceutical acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising therapeutically effective amount of a compound ofclaim 1 having formula (I) or a pharmaceutically acceptable saltthereof, in combination with a pharmaceutically acceptable carrier.